mycophenolic-acid and Proteinuria

Topics: Cyclophosphamide; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Lupus Nephritis; Mycophenolic Acid; Proteinuria; Treatment Outcome

Renal involvement in patients with systemic lupus erythematosus can lead to significant complications including end-stage renal disease. Treatment of lupus nephritis has evolved over the last several decades, but despite this evolution, many patients fail to achieve remission and often progress to end-stage kidney disease or carry a burden of adverse side effects related to treatment.. The recent findings from AURORA 1 and BLISS LN trials led the FDA to approve voclosporin and belimumab for the treatment of lupus nephritis. The AURORA 1 trial demonstrated that voclosporin, a second-generation calcineurin inhibitor, effectively lowers proteinuria in patients with lupus nephritis, when added to mycophenolate mofetil with a better safety profile, compared with other calcineurin inhibitors. The BLISS LN trial revealed better control of disease and lower risk of progression to end stage kidney disease (ESKD) and relapses in patients treated with belimumab in addition to standard therapy.. Both voclosporin and belimumab are costly and have not shown any early evidence to revolutionize practice in the management of lupus nephritis. Until more data are made available with future studies or other cost-effective treatment options become available, the widespread adoption and utility of these novel agents remains limited.

Topics: Female; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Lupus Nephritis; Male; Mycophenolic Acid; Proteinuria; Treatment Outcome

IgA nephropathy is the most common glomerulonephritis world-wide. IgA nephropathy causes end-stage kidney disease (ESKD) in 15% to 20% of affected patients within 10 years and in 30% to 40% of patients within 20 years from the onset of disease. This is an update of a Cochrane review first published in 2003 and updated in 2015.. To determine the benefits and harms of immunosuppression strategies for the treatment of IgA nephropathy.. We searched the Cochrane Kidney and Transplant Register of Studies up to 9 September 2019 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.. We included randomised controlled trials (RCTs) and quasi-RCTs of treatment for IgA nephropathy in adults and children and that compared immunosuppressive agents with placebo, no treatment, or other immunosuppressive or non-immunosuppressive agents.. Two authors independently assessed study risk of bias and extracted data. Estimates of treatment effect were summarised using random effects meta-analysis. Treatment effects were expressed as relative risk (RR) and 95% confidence intervals (95% CI) for dichotomous outcomes and mean difference (MD) and 95% CI for continuous outcomes. Risks of bias were assessed using the Cochrane tool. Evidence certainty was evaluated using GRADE methodology.. Fifty-eight studies involving 3933 randomised participants were included. Six studies involving children were eligible. Disease characteristics (kidney function and level of proteinuria) were heterogeneous across studies. Studies evaluating steroid therapy generally included patients with protein excretion of 1 g/day or more. Risk of bias within the included studies was generally high or unclear for many of the assessed methodological domains. In patients with IgA nephropathy and proteinuria > 1 g/day, steroid therapy given for generally two to four months with a tapering course probably prevents the progression to ESKD compared to placebo or standard care (8 studies; 741 participants: RR 0.39, 95% CI 0.23 to 0.65; moderate certainty evidence). Steroid therapy may induce complete remission (4 studies, 305 participants: RR 1.76, 95% CI 1.03 to 3.01; low certainty evidence), prevent doubling of serum creatinine (SCr) (7 studies, 404 participants: RR 0.43, 95% CI 0.29 to 0.65; low certainty evidence), and may lower urinary protein excretion (10 studies, 705 participants: MD -0.58 g/24 h, 95% CI -0.84 to -0.33;low certainty evidence). Steroid therapy had uncertain effects on glomerular filtration rate (GFR), death, infection and malignancy. The risk of adverse events with steroid therapy was uncertain due to heterogeneity in the type of steroid treatment used and the rarity of events. Cytotoxic agents (azathioprine (AZA) or cyclophosphamide (CPA) alone or with concomitant steroid therapy had uncertain effects on ESKD (7 studies, 463 participants: RR 0.63, 95% CI 0.33 to 1.20; low certainty evidence), complete remission (5 studies; 381 participants: RR 1.47, 95% CI 0.94 to 2.30; very low certainty evidence), GFR (any measure), and protein excretion. Doubling of serum creatinine was not reported. Mycophenolate mofetil (MMF) had uncertain effects on the progression to ESKD, complete remission, doubling of SCr, GFR, protein excretion, infection, and malignancy. Death was not reported. Calcineurin inhibitors compared with placebo or standard care had uncertain effects on complete remission, SCr, GFR, protein excretion, infection, and malignancy. ESKD and death were not reported. Mizoribine administered with renin-angiotensin system inhibitor treatment had uncertain effects on progression to ESKD, complete remission, GFR, protein excretion, infection, and malignancy. Death and SCr were not reported. Leflunomide followed by a tapering course with oral prednisone com. In moderate certainty evidence, corticosteroid therapy probably prevents decline in GFR or doubling of SCr in adults and children with IgA nephropathy and proteinuria. Evidence for treatment effects of immunosuppressive agents on death, infection, and malignancy is generally sparse or low-quality. Steroid therapy has uncertain adverse effects due to a paucity of studies. Available studies are few, small, have high risk of bias and generally do not systematically identify treatment-related harms. Subgroup analyses to identify specific patient characteristics that might predict better response to therapy were not possible due to a lack of studies. There is no evidence that other immunosuppressive agents including CPA, AZA, or MMF improve clinical outcomes in IgA nephropathy.

Topics: Adult; Calcineurin Inhibitors; Cause of Death; Child; Confidence Intervals; Creatinine; Drug Administration Schedule; Drug Therapy, Combination; Glomerular Filtration Rate; Glomerulonephritis, IGA; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Leflunomide; Mycophenolic Acid; Proteinuria; Randomized Controlled Trials as Topic; Remission Induction; Ribonucleosides; Risk; Steroids

Chronic kidney disease (CKD) is increasingly recognized in pregnant patients. Three characteristics are associated with a risk of preterm delivery or small for gestational age babies; kidney function reduction, hypertension, and proteinuria. In pregnancy, the anti-proteinuric agents (ACE-angiotensin converting enzyme-inhibitors or ARBS -angiotensin receptor blockers) have to be discontinued for their potential teratogenicity, and there is no validated approach to control proteinuria. Furthermore, proteinuria usually increases as an effect of therapeutic changes and pregnancy-induced hyperfiltration. Based on a favourable effect of low-protein diets on proteinuria and advanced CKD, our group developed a moderately protein-restricted vegan-vegetarian diet tsupplemented with ketoacids and aminoacids for pregnant patients. This report describes the results obtained in three pregnant patients with normal renal function, nephrotic or sub-nephrotic proteinuria, and biopsy proven diagnosis of focal segmental glomerulosclerosis, a renal lesion in which hyperfiltration is considered of pivotal importance (case 1: GFR (glomerular filtration rate): 103 mL/min; proteinuria 2.1 g/day; albumin 3.2 g/dL; case 2: GFR 86 mL/min, proteinuria 3.03 g/day, albumin 3.4 g/dL; case 3: GFR 142 mL/min, proteinuria 6.3 g/day, albumin 3.23 g/dL). The moderately restricted diet allowed a stabilisation of proteinuria in two cases and a decrease in one. No significant changes in serum creatinine and serum albumin were observed. The three babies were born at term (38 weeks + 3 days, female, weight 3180 g-62th centile; 38 weeks + 2 days, female, weight 3300 g-75th centile; male, 38 weeks + 1 day; 2770 g-8th centile), thus reassuring us of the safety of the diet. In summary, based on these three cases studies and a review of the literature, we suggest that a moderately protein-restricted, supplemented, plant-based diet might contribute to controlling proteinuria in pregnant CKD women with focal segmental glomerulosclerosis. However further studies are warranted to confirm the potential value of such a treatment strategy.

Topics: Adult; Amino Acids; Biomarkers; Biopsy; Black People; Cyclophosphamide; Cyclosporine; Diet, Protein-Restricted; Diet, Vegan; Diet, Vegetarian; Female; Glomerular Filtration Rate; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Keto Acids; Kidney; Male; Mycophenolic Acid; Pregnancy; Proteinuria; Renal Insufficiency, Chronic; White People

IgA nephropathy (IgAN) is a leading cause of CKD and renal failure. Recent international collaborative efforts have led to important discoveries that have improved our understanding of some of the key steps involved in the immunopathogenesis of IgAN. Furthermore, establishment of multicenter networks has contributed to rigorous design and execution of clinical trials that have provided important insights regarding immunotherapy in IgAN. In this article, we review emerging developments in clinical and translational IgAN research and describe how these novel findings will influence future strategies to improve the outcome of patients with IgAN.

Topics: Adrenal Cortex Hormones; Conservative Treatment; Drug Therapy, Combination; Glomerulonephritis, IGA; Hematuria; Humans; Immunologic Factors; Mycophenolic Acid; Phenotype; Proteinuria; Renal Insufficiency, Chronic; Rituximab

Focal segmental glomerulosclerosis (FSGS) is the histologic end point of many disease processes that affect the kidney. Clinically, adults with FSGS present with proteinuria that may be accompanied by the nephrotic syndrome. Once identifiable (secondary) causes are excluded, the diagnosis of idiopathic FSGS, a challenging glomerular disease to understand and manage, is made. On the basis of mostly retrospective data, first-line treatment for idiopathic FSGS patients with nephrotic-range proteinuria is a prolonged course of corticosteroids. However, steroid resistance is common and portends an increased risk of long-term decline in kidney function and end-stage kidney disease in these patients compared with responders. Multiple other immunosuppression regimens have been used in steroid-resistant FSGS, some of which have been studied in randomized controlled trials. Here, we review the data on the treatment for idiopathic FSGS in adults.

Topics: Adult; Angiotensin II Type 2 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Glomerulosclerosis, Focal Segmental; Glucocorticoids; Humans; Hypertension; Immunosuppressive Agents; Mycophenolic Acid; Nephrotic Syndrome; Proteinuria; Treatment Outcome

IgA nephropathy is the most common primary glomerular disease worldwide and also the most frequent cause of kidney failure. Mycophenolate mofetil (MMF) is a selective immunosuppressant widely used in many autoimmune diseases. However, the benefits and risks of MMF for the treatment of IgA nephropathy remain uncertain.. A systematic review and meta-analysis of randomized controlled trials (RCTs) was performed to assess the efficacy and safety of MMF in IgA nephropathy patients, using the statistical software Review Manager 5.1.. Eight RCTs involving 357 patients were identified and included in this review. Overall, no statistical difference was found in the therapeutic effect of MMF treatment compared with other therapies. MMF had no significant effects on reducing proteinuria or protecting renal function. However, subgroup analysis indicated that relatively short-term therapy (<18 months) might be beneficial in IgA nephropathy patients while longer term MMF use conferred no advantage. There was also no statistical difference between MMF and control groups in the incidence of side effects. When compared with other immunosuppressants, MMF was considered superior to cyclophosphamide in terms of better therapeutic effects and fewer adverse reactions, but no difference was found between MMF and leflunomide.. Our current evidence indicates that a relatively short course of MMF may be beneficial in treating IgA nephropathy. However, high-quality RCTs with large sample size as well as a well-designed study to evaluate the long-term effects of MMF are needed to further evaluate the efficacy and safety of MMF in this disease.

Topics: Creatinine; Drug Administration Schedule; Glomerulonephritis, IGA; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Mycophenolic Acid; Proteinuria

Idiopathic focal and segmental glomerular sclerosis is a frequent cause of nephrotic syndrome and end-stage renal disease. The pathogenesis is still unknown, although the body of evidence suggests that focal and segmental glomerular sclerosis is caused by a not clearly identified circulating factor that alters the permselectivity of the glomerular barrier. Proteinuria is followed by podocyte injury. Glucocorticoids, calcineurin inhibitors, cytotoxic agents and mycophenolate mofetil, either given alone or in combination, may obtain complete or partial remission of proteinuria in 50-60% of patients and protect them from end-stage renal disease, but the remaining patients are resistant to the available drugs. A number of new drugs, including rituximab, galactose and antifibrotic agents, are under investigation.

Topics: Adult; Antibodies, Monoclonal, Murine-Derived; Calcineurin Inhibitors; Glomerulosclerosis, Focal Segmental; Glucocorticoids; Humans; Kidney Failure, Chronic; Mycophenolic Acid; Nephrotic Syndrome; Proteinuria; Rituximab

We report a case of pediatric severe aplastic anemia (SAA), where the patient underwent allogenic bone marrow transplantation (BMT) from an HLA mismatched family donor and developed focal segmental glomerulosclerosis (FSGS). An 11-year-old girl, who had SAA, was admitted to our hospital in 200X. Complete remission was not attained after immunosuppressive therapy with rabbit-antithymocyte globulin, prednisolone (PSL), and cyclosporine A (CsA). Eight months after being diagnosed with SAA, she underwent an allogenic BMT from her mother. We used a combination of 2-Gy total body irradiation, fludarabine, and cyclophosphamide as a preparative regimen prior to the BMT. CsA and PSL were used as prophylaxis against GVHD. Since the BMT did not lead to successful engraftment, the patient required two peripheral blood stem cell transplantations (PBSCT). Engraftment was sustained and no acute or chronic GVHD was observed. Six months after the first BMT, she developed clinical nephrotic syndrome despite the continuous PSL and CsA treatments. Renal biopsy revealed a total of 12 glomeruli, one of which showed segmental sclerosis. Electron microscopy revealed diffuse effacement of the foot processes. These findings were consistent with FSGS, and she was treated with mycophenolate mofetil (MMF) in combination with PSL instead of CsA, which greatly reduced her proteinuria. In general, the most common type of nephropathy after HSCT is GVHD-related nephrotic syndrome, and the most common pathological finding is membranous nephropathy or minimal change. FSGS without GVHD after HSCT, such as that observed in our case, is rare. In this case, the renal damage appears to have been caused by the effect of circulating permeability factors with immunity change after HSCT. This case demonstrates the importance of renal biopsy as a guide to determine the extent of renal damage and as an aid to determine the possible response to therapy.

Topics: Anemia, Aplastic; Biopsy; Child; Cyclosporine; Female; Glomerulosclerosis, Focal Segmental; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Kidney Glomerulus; Microscopy, Electron; Mycophenolic Acid; Nephrotic Syndrome; Proteinuria; Treatment Outcome

A pooled post-hoc analysis of the phase 3, randomized, placebo-controlled BLISS trials (1684 patients with active systemic lupus erythematosus (SLE)) was performed to evaluate the effect of belimumab on renal parameters in patients with renal involvement at baseline, and to explore whether belimumab offered additional renal benefit to patients receiving mycophenolate mofetil at baseline. In addition to belimumab or placebo, all patients received standard SLE therapy. Patients with severe active lupus nephritis were excluded from the trials. Over 52 weeks, rates of renal flare, renal remission, renal organ disease improvement (assessed by Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index and British Isles Lupus Assessment Group), proteinuria reduction, grade 3/4 proteinuria, and serologic activity favored belimumab, although the between-group differences in most renal outcomes were not significant. Among the 267 patients with renal involvement at baseline, those receiving mycophenolate mofetil or with serologic activity at baseline had greater renal organ disease improvement with belimumab than with placebo. Limitations of this analysis included the small patient numbers and the post-hoc nature of this pooled analysis. The results suggest that belimumab may offer renal benefit in patients with SLE. Further study is warranted in patients with severe active lupus nephritis.

Topics: Antibodies, Monoclonal, Humanized; Asia; Biomarkers; Disease Progression; Drug Therapy, Combination; Europe; Humans; Immunosuppressive Agents; Latin America; Lupus Erythematosus, Systemic; Lupus Nephritis; Mycophenolic Acid; North America; Proteinuria; Remission Induction; Severity of Illness Index; Time Factors; Treatment Outcome

The use of mycophenolate mofetil (MMF) has been extended from renal transplantation to the treatment of glomerulonephritis. MMF has been used in patients with steroid- and ciclosporin A (CsA)-dependent or -resistant idiopathic nephrotic syndrome and in patients with deteriorating renal function or adverse reactions to other drugs. MMF has been also used in patients with membranous and IgA nephropathy after failure of other regimens as well as initial treatment.. The rationale of MMF treatment in primary glomerulonephritis is based in its antifibrotic and antiproteinuric effects. The mechanism of action is described; the results of cohort and randomized trials in minimal change disease, focal segmental glomerulosclerosis, idiopathic membranous nephropathy and IgA nephropathy are presented along with the adverse reactions profile and the expert opinion.. This is an up-to-date review providing insight on this novel agent that is increasingly used in the therapeutics of primary glomerulonephritis.. Although the results are conflicting, MMF seems to be effective at least in some patients, who do not respond to corticosteroids, ciclosporin or cytotoxic drugs. However, the experience with MMF in primary glomerulonephritis is limited and further research is required in order to establish MMF in the treatment of patients with glomerular disease.

Topics: Animals; Clinical Trials as Topic; Enzyme Inhibitors; Fibrosis; Glomerulonephritis; Humans; Mycophenolic Acid; Proteinuria

Worldwide, IgA nephropathy (IgAN) is the most common type of glomerulonephritis. Mycophenolate mofetil (MMF) is relatively selective for lymphocytes and inhibits antibody production by B cells more than other immunosuppressants. Several randomized controlled trials (RCTs) have analyzed the role of MMF in patients with IgAN. We conducted this meta-analysis of all available RCTs to ascertain the benefits and risks of MMF treatment in comparison with placebos or steroids in patients with IgAN.. The studies were identified by extended computer-based searches of the PubMed database (April, 2008) and the Cochrane Library, without language restriction. References in Medline-cited studies were reviewed to identify additional reports not indexed by Medline. RCTs comparing treatment of IgAN with mycophenolate against placebo or steroids were included in the analysis.. We identified 32 potentially relevant articles, but only 4 RCTs, which had enrolled a total of 168 patients, were included. Our meta-analysis demonstrated that MMF treatment did not have statistically significant effects in reducing proteinuria or protecting renal function in patients with IgAN.. The currently available evidence does not support the routine use of MMF in patients with IgAN. Larger international collaborations should be put in place to further address this issue.

Topics: Creatinine; Glomerulonephritis, IGA; Humans; Immunosuppressive Agents; Mycophenolic Acid; Proteinuria; Randomized Controlled Trials as Topic; Renal Replacement Therapy

Mycophenolate mofetil (MMF) has been used successfully as an immunosuppressive medication in transplantation for over a decade. Owing to its efficacy and relatively benign adverse effect profile, its use has been investigated in the treatment of several glomerular diseases, as we describe in this Review. Of these, MMF has most extensively been studied in lupus nephritis. Randomized controlled trials have documented the value of MMF in both induction and maintenance therapy for severe lupus nephritis in several different geographic and ethnic populations, and have defined its potential toxicity. In minimal-change disease, focal segmental glomerulosclerosis and membranous nephropathy, promising but limited data on MMF treatment exist from small retrospective and prospective studies. Ongoing, larger, prospective trials, such as the NIH trial in focal segmental glomerulosclerosis, might clarify the value of MMF in the treatment of this disease. The efficacy of MMF in IgA nephropathy remains unclear, despite several small, controlled trials. Conflicting results might reflect differences in the disease process, differences in MMF metabolism, or varying responses to the immunosuppressive agent in different populations. Only through large, collaborative, controlled trials will the true role of MMF be defined for each glomerular disease.

Topics: Creatinine; Glomerulonephritis; Humans; Immunosuppressive Agents; Lupus Nephritis; Mycophenolic Acid; Proteinuria; Randomized Controlled Trials as Topic; Recurrence

Membranous nephropathy, focal segmental glomerulosclerosis and IgA nephropathy are the most commonly recognized types of primary glomerulonephritis that progress to end-stage renal disease. Persistent proteinuria is a major determinant of such progression. Reduction of proteinuria slows progression of renal disease and improves renal survival, but many of the agents used to reduce proteinuria carry a considerable risk of toxicity. The assessment of benefit versus risk of these medications can be further complicated by the temporal disconnect between the onset of benefit and of serious adverse events. In addition, relapses are common in these disorders and there is often a need for retreatment. Such retreatment might lead to repeated and/or prolonged drug exposure and to the oversight or underestimation of the cumulative dose of these agents because of the potentially extended interval between relapses. Consequently, it is very important to constantly review each patient's status and take into account their age, comorbid conditions and cumulative drug exposure when assessing treatment options. The potentially delayed development of adverse events also emphasizes the need for long-term surveillance of patients who receive immunosuppressive treatment for glomerular disease, often well beyond their drug exposure period and even when the treatment has been successful.

Topics: Alkylating Agents; Calcineurin Inhibitors; Glomerulonephritis; Glomerulonephritis, IGA; Glomerulonephritis, Membranous; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Mycophenolic Acid; Proteinuria; Remission Induction; Risk Factors

The aim of this study was to determine the effectiveness of mycophenolate mofetil (MMF) in IgA nephropathy (IgAN).. A search through Cochrane Library, EMBASE and PubMed was carried out. Randomised controlled trials (RCTs), which compared MMF with conventional treatments, were identified. Patients' baseline, treatment strategies and study end-points were compared.. Four RCTs (168 patients) were selected. All patients had histologically-confirmed IgAN and proteinuria greater than 1 g/day. The follow-up duration ranged from 1.5 to 3.0 years. MMF was used at a titrated dose of 1-2 g/day. In the two trials with subjects having moderate to high risk for progressive disease, MMF did not demonstrate any significant difference in retarding the decline in renal function and proteinuria reduction. One trial concluded that there was a trend towards worse outcomes when MMF was used in moderately-advanced disease. Only one trial involving subjects with less advanced disease (reflected by a favourable histological grade) showed a significant decrease in proteinuria in the MMF-treated group. No serious adverse events occurred in all the four trials using MMF.. No benefit was seen in moderately-advanced IgAN treated with MMF. In a selected group of patients with less advanced disease, MMF was effective in proteinuria reduction. Larger randomised studies are needed to confirm or reject these results.

Topics: Creatinine; Glomerulonephritis, IGA; Humans; Immunosuppressive Agents; Kidney; Kidney Failure, Chronic; Mycophenolic Acid; Placebos; Proteinuria; Quality Control; Randomized Controlled Trials as Topic; Remission Induction; Treatment Outcome

Thirty to forty percent of patients with idiopathic membranous nephropathy have persistent heavy proteinuria and may progress to end-stage kidney disease in 5 - 15 years. The ideal treatment for these patients is a matter of debate. Several nonspecific immunosuppressive regimens have been suggested with the aim of reducing proteinuria and to improve outcome, but all are burdened by significant toxicity. Therefore, more specific and less toxic therapies are needed. Promising results have been recently obtained with rituximab, a monoclonal antibody against the CD20 antigen of B lymphocytes that is able to deplete these cells and, thus, neoformation of pathogenetic antibodies. Other novel drugs, such as adrenocorticotropic hormone, mycophenolate mofetil and eculizumab have been proposed. This paper reviews the safety/efficacy profile of various agents that have been proposed as therapy for this disease, with particular focus on the latest, more specific and hypothesis-driven approaches.

Topics: Adrenocorticotropic Hormone; Alkylating Agents; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Antigens, CD20; Calcineurin Inhibitors; Glomerulonephritis, Membranous; Glucocorticoids; Humans; Immunosuppressive Agents; Mycophenolic Acid; Proteinuria; Rituximab

A prolonged course with corticosteroids represents the first therapeutic approach for nephrotic patients with focal segmental glomerulosclerosis (FSGS). In patients with contraindications to steroids or in those who do not respond to steroids or cyclosporine, cytotoxic agents, mycophenolate mofetil (MMF), plasmapheresis, and low-density lipoprotein (LDL) apheresis have been tried as alternative treatments. A short-term treatment with cytotoxic agents often is ineffective in steroid-resistant patients However, an aggressive and prolonged treatment with cytotoxic agents combined with corticosteroids proved to be effective in more than half of steroid-resistant children. In adults, the response to cytotoxic agents was good in steroid-responsive patients, but was poor in steroid-resistant patients. Better results were observed when cytotoxic therapy was prolonged for several months. The problem with these drugs is that long-term immunosuppression may be complicated by severe side effects including a major risk for cancer. Uncontrolled studies reported that MMF can induce some reduction of proteinuria, but complete remission of proteinuria was rare and no data on long-term follow-up evaluation with this drug are available. Good results have been reported with plasmapheresis, immunoadsorption, and lipopheresis. However, all the reports were uncontrolled, small sized, and with short-term follow-up evaluation. In conclusion, there are several therapeutic options for patients who respond to steroids and have further relapses of nephrotic syndrome, but how to treat steroid-resistant patients is still a matter of debate. Nevertheless, a 6-month trial with cytotoxic agents or MMF can be offered to steroid-resistant patients to identify the few patients who respond to these agents. The preliminary results with plasmapheresis or lipopheresis are promising but further studies are needed to assess the role of these treatments.

Topics: Disease Progression; Dose-Response Relationship, Drug; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Mycophenolic Acid; Nephrotic Syndrome; Proteins; Proteinuria

In this review, therapeutic trials for treatment of IgA nephropathy (Berger's disease) are reviewed and discussed. No disease-specific therapy exists. For treatment of hypertensive patients, angiotensin converting enzyme (ACE) inhibitors are preferred. They also decrease proteinuria and probably slow disease progression. However, there are still no controlled data on the effectiveness of ACE-inhibitors in the absence of hypertension or proteinuria. Renewed enthusiasm for treatment with fish oil arose after the publication of a randomized controlled trial in 1994 and long-term follow-up data of the trial cohort in 1998. Corticoid therapy in IgA nephropathy has been advocated for patients with nephrotic syndrome or crescentic disease. A recent non-randomised trial with long-term follow-up suggests that, in the presence of moderate proteinuria, corticosteroids may ameliorate renal function if administered before the creatinine clearance has decreased below 70 ml/min. Preliminary data suggest that mycophenolate mofetil (MMF) may reduce the risk of clinically significant IgA nephropathy recurring in kidney allografts. Many other promising treatment approaches have been tested, but in most instances results are insufficient for unequivocal conclusions. Several randomized controlled clinical trials are currently testing prednisone, fish oil, ACE-inhibitors, cyclophosphamide, MMF and vitamin E. In the absence of a disease-specific treatment, control of hypertension, proteinuria and probably dyslipidemia are pivotal. Chronic or recurrent infection including ton-sillitis should be treated effectively. Control of daily protein intake to 0.7-0.8 g/kg body weight may retard disease progression.

Topics: Angiotensin-Converting Enzyme Inhibitors; Anti-Inflammatory Agents; Cyclosporine; Disease Progression; Fish Oils; Glomerulonephritis, IGA; Humans; Hypertension; Immunosuppressive Agents; Mycophenolic Acid; Proteinuria; Steroids; Treatment Outcome

The role of mycophenolate mofetil (MMF) in management of immunoglobulin A nephropathy (IgAN) remains highly controversial.. To evaluate the efficacy and safety of MMF in patients with IgAN at high risk of kidney function loss.. This randomized clinical trial with open-label, blinded end-point design was conducted among adults with IgAN, proteinuria greater than 1.0 g/d, and estimated glomerular filtration rate (eGFR) greater than 30 and less than 60 mL/min/1.73m2 or with persistent hypertension from September 2013 to December 2015. During a 3-month run-in period, 238 patients received optimized supportive care (SC), including losartan. Patients with a urinary protein excretion rate of 0.75 g/d or greater despite of 3 months optimized SC were enrolled into the trial for 3 years. Survivors of the trial who did not receive dialysis or transplant were followed up after the trial for a median (IQR) of 60 (47-76) months. Data were analyzed from March through June 2022.. A total of 170 participants were randomized in a 1:1 ratio to receive MMF (initially, 1.5 g/d for 12 months, maintained at 0.75-1.0 g for at least 6 months) plus SC or SC alone.. The primary outcomes were (1) a composite of doubling of serum creatinine, end-stage kidney disease (dialysis, transplant, or kidney failure without receiving kidney replacement therapy), or death due to kidney or cardiovascular cause and (2) progression of chronic kidney disease.. Among 170 randomized patients (mean [SD] age 36.6 [9.4] years; 94 [55.3%] male patients), 85 patients received MMF with SC and 85 patients received SC alone. The mean (SD) eGFR was 50.1 (17.9) mL/min/1.73m2 and mean (SD) proteinuria level was 1.9 (1.7) g/d; 168 patients (98.8%) completed the trial, and 157 participants (92.4%) survived and did not receive dialysis or transplant. Primary composite outcome events occurred in 6 patients (7.1%) in the MMF group and 18 patients (21.2%) in the SC group (adjusted hazard ratio [aHR], 0.23; 95% CI, 0.09-0.63). Progression of chronic kidney disease occurred in 7 participants (8.2%) in the MMF group and 23 participants (27.1%) in the SC group (aHR, 0.23; 95% CI, 0.10-0.57). The effect of MMF treatment on primary outcomes was consistent across prespecified subgroups, with no significant interaction per subgroup. During posttrial follow-up, annual loss of eGFR accelerated after discontinuation of MMF; mean (SD) annual eGFR loss during the study period was 2.9 (1.0) mL/min/1.73m2 in the MMF group and 6.1 (1.2) mL/min/1.73m2 among 66 patients in the MMF group who discontinued MMF after the trial. Serious adverse events were not more frequent with MMF vs SC alone.. This study found that addition of MMF to SC compared with SC alone significantly reduced risk of disease progression among patients with progressive IgAN.. ClinicalTrials.gov Identifier: NCT01854814.

Topics: Adult; Female; Glomerulonephritis, IGA; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Male; Middle Aged; Mycophenolic Acid; Proteinuria; Renal Dialysis

Remission of proteinuria has been shown to be associated with lower rates of kidney disease progression among people with focal segmental glomerulosclerosis (FSGS). The goal of this study was to evaluate whether reductions in proteinuria after treatment are associated with greater kidney survival.. Cohort analysis of clinical trial participants.. Patients with steroid-resistant FSGS enrolled in a randomized treatment trial that compared cyclosporine with mycophenolate mofetil plus dexamethasone.. Reduction in proteinuria measured during 26 weeks after initiating treatment.. Repeated assessments of estimated glomerular filtration rate (eGFR) and time to a composite outcome of kidney failure or death assessed between 26 weeks and 54 months after randomization.. Multivariable linear mixed-effects models with participant-specific slope and intercept to estimate the association of change in proteinuria over 26 weeks while receiving treatment with the subsequent slope of change in eGFR. Multivariable time-varying Cox proportional hazards models were used to estimate the association of changes in proteinuria with time to the composite outcome.. 138 of 192 trial participants were included. Changes in proteinuria over 26 weeks were significantly related to eGFR slope. A 1-unit reduction in log-transformed urinary protein-creatinine ratio was associated with a 3.90mL/min/1.73m. Limited to individuals with steroid-resistant FSGS followed up for a maximum of 5 years.. These findings provide evidence for the benefit of urinary protein reduction in FSGS. Reductions in proteinuria warrant further evaluation as a potential surrogate for preservation of kidney function that may inform the design of future clinical trials.

Topics: Adolescent; Child; Cohort Studies; Creatinine; Cyclosporine; Dexamethasone; Disease Progression; Female; Glomerular Filtration Rate; Glomerulosclerosis, Focal Segmental; Glucocorticoids; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Male; Mortality; Mycophenolic Acid; Prognosis; Proportional Hazards Models; Proteinuria; Remission Induction; Tissue Survival; Treatment Outcome; Young Adult

Topics: Adult; Arterioles; Blood Pressure; Cyclosporine; Diarrhea; Drug Resistance; Drug Therapy, Combination; Eye Diseases, Hereditary; Female; Fibrosis; Glomerular Filtration Rate; Glomerulosclerosis, Focal Segmental; Glucocorticoids; Humans; Hyalin; Immunosuppressive Agents; Intestinal Diseases; Male; Mycophenolic Acid; Prednisolone; Prospective Studies; Proteinuria; Skin Abnormalities; Treatment Outcome; Vascular Diseases

To study the efficacy and safety of mycophenolate mofetil (MMF) versus cyclophosphamide (CTX) in the treatment of children with Henoch-Schönlein purpura nephritis (HSPN) and nephrotic-range proteinuria.. A prospective clinical trial was conducted in 68 pediatric patients who were admitted to the Department of Nephrology, Children's Hospital Affiliated to Capital Institute of Pediatrics and who were diagnosed with HSPN and nephrotic-range proteinuria from August 2016 to November 2019. The patients were randomly divided into two groups:MMF treatment (. At months 3, 6, and 12 of treatment, there was no significant difference in the complete remission rate and the response rate between the MMF treament and CTX treatment groups (. MMF and CTX have similar efficacy and safety in the treatment of HSPN children with nephrotic-range proteinuria.

Topics: Child; Cyclophosphamide; Humans; IgA Vasculitis; Immunosuppressive Agents; Mycophenolic Acid; Nephritis; Prospective Studies; Proteinuria; Retrospective Studies

Appropriate immunosuppressive therapy for patients with idiopathic membranous nephropathy (MN) remains controversial. The effect of mycophenolate mofetil (MMF) versus cyclosporine (CsA) combined with low-dose corticosteroids was evaluated in patients with idiopathic MN in a multi-center randomized trial (www.ClinicalTrials.gov NCT01282073).. A total of 39 biopsy-proven idiopathic MN patients with severe proteinuria were randomly assigned to receive MMF combined with low-dose corticosteroids (MMF group) versus CsA combined with low-dose corticosteroids (CsA group), respectively, and followed up for 48 weeks. Complete or partial remission rate of proteinuria and estimated glomerular filtration rate (eGFR) at 48 weeks were compared.. The level of proteinuria at baseline and at 48 weeks was 8.9 ± 5.9 and 2.1 ± 3.1 g/day, respectively, in the MMF group compared to 8.4 ± 3.5 and 3.2 ± 5.7 g/day, respectively, in the CsA group. In total, 76.1% of the MMF group and 66.7% of the CsA group achieved remission at 48 weeks (95% confidence interval, -0.18 to 0.38). There was no difference in eGFR between the two groups. Anti-phospholipase A2 receptor Ab levels at baseline decreased at 48 weeks in the complete or partial remission group (P = 0.001), but were unchanged in the no-response group. There were no significant differences between the two groups in changes in the Gastrointestinal Symptom Rating Scale and Gastrointestinal Quality of Life Index scores from baseline to 48 weeks.. In combination with low-dose corticosteroids, the effect of MMF may not be inferior to that of CsA in patients with idiopathic MN, with similar adverse effects including gastrointestinal symptoms. Trial registry at ClinicalTrials.gov (NCT01282073).

Topics: Adrenal Cortex Hormones; Adult; Aged; Antibiotics, Antineoplastic; Antibodies; Cyclosporine; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Proteinuria; Quality of Life; Receptors, Phospholipase A2; Remission Induction; Treatment Outcome

The objective of this study is to evaluate the efficacy of a tightly controlled renoprotective protocol in systemic lupus erythematosus (SLE) patients with persistent proteinuria.. Thirteen SLE patients with nephritis and persistent proteinuria (>1 g/24 hours) were included. The protocol consisted of regular clinical evaluations every two weeks to assess blood pressure (BP, target <130/80 mmHg), adherence to therapy, diet and smoking. No change in immunosuppressive drugs was allowed but reduction of glucocorticoid dose was permitted if indicated. Clinical, laboratory and treatment evaluations were performed at baseline and at the end of the study (after three months).. SLE patients had a mean age of 37.85 ± 7.68 years and disease duration of 9.85 ± 7.29 years. At baseline, patients had a mean duration of maintenance therapy of 10.38 ± 7.56 months, 12 with mycophenolate mofetil (92.3%) and one with azathioprine (7.7%). At least one dose optimization of antihypertensive regimen was required in all patients during the study. Seven patients (53.8%) had BP>130/80mmHg at baseline. At the end, 11 patients (84.6%) achieved stable BP target; 92.3% were using an angiotensin-converting enzyme inhibitor, 53.9% an angiotensin receptor blocker, and 46.2% were using combined therapy. All patients had a significant reduction in proteinuria levels (2.26 ± 1.09 vs 0.88 ± 0.54 g/24 hours, p < 0.001) and 61.5% achieved proteinuria <1 g/24 hours. A significant decrease in mean prednisone dose was observed (10.96 ± 6.73 vs 5.38 ± 3.36 mg/day, p = 0.013) as well as mean Systemic Lupus Erythematosus Disease Activity Index score (4.38 ± 0.72 vs 3.08 ± 1.86, p = 0.043). No significant changes were identified in serum creatinine, albumin, potassium, complement 3 and complement 4 levels ( p > 0.05).. This study provides evidence that a tightly controlled renoprotective protocol is effective in reducing persistent proteinuria in lupus nephritis. The concomitant reduction of prednisone without any change in immunosuppression reinforces the importance of strategies beyond the treatment of nephritis activity.

Topics: Adult; Azathioprine; Blood Pressure; Brazil; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Lupus Nephritis; Male; Middle Aged; Mycophenolic Acid; Prednisone; Proteinuria; Severity of Illness Index

Observational studies suggest that patients with immunoglobulin A nephropathy (IgAN) with active proliferative lesions show a good response to immunosuppressive treatment.. Multicenter, prospective, randomized, controlled trial.. 176 patients with IgAN with active proliferative lesions (cellular and fibrocellular crescents, endocapillary hypercellularity, or necrosis), proteinuria with protein excretion ≥ 1.0g/24h, and estimated glomerular filtration rate > 30mL/min/1.73m. Mycophenolate mofetil (MMF) group: MMF, 1.5g/d, for 6 months and prednisone, 0.4 to 0.6mg/kg/d, for 2 months and then tapered by 20% per month for the next 4 months; prednisone group: prednisone, 0.8 to 1.0mg/kg/d, for 2 months and then tapered by 20% per month for the next 4 months. All patients were followed up for another 6 months.. The primary end point was complete remission rate at 6 and 12 months.. Not all participants were treated with renin-angiotensin system blockers, relatively short follow-up.. MMF plus prednisone versus full-dose prednisone did not differ in reducing proteinuria, but patients treated with the former had fewer adverse events in patients with IgAN with active proliferative lesions.

Topics: Adult; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Glomerulonephritis, IGA; Glucocorticoids; Humans; Immunosuppressive Agents; Male; Mycophenolic Acid; Prednisone; Proteinuria; Remission Induction; Treatment Outcome

To compare the efficacy of tacrolimus (TAC) and mycophenolate mofetil (MMF) for the initial therapy of lupus nephritis (LN).. This is an open randomised controlled parallel group study.. Adult patients with biopsy-confirmed active LN (class III/IV/V) were randomised to receive prednisolone (0.6 mg/kg/day for 6 weeks and tapered) in combination with either TAC (0.06-0.1 mg/kg/day) or MMF (2-3 g/day) for 6 months. Good responders were shifted to azathioprine for maintenance. The primary outcome was the rate of complete renal response (CR) at 6 months and the secondary outcomes included partial renal response, renal flares and decline of renal function over time.. 150 patients (92% women; aged 35.5±12.8 years; 81% class III/IV) were randomised (76 MMF, 74 TAC). At month 6, the rate of CR was 59% in the MMF and 62% in the TAC group (treatment difference: 3.0% (-12%, 18%); p=0.71). Major infective episodes occurred in 9.2% patients treated with MMF and in 5.4% patients treated with TAC (p=0.53). Maintenance therapy with azathioprine was given to 79% patients. After 60.8±26 months, proteinuric and nephritic renal flares developed in 24% and 18% of patients in the MMF group and 35% (p=0.12) and 27% (p=0.21) in the TAC group, respectively. The cumulative incidence of a composite outcome of decline of creatinine clearance by ≥30%, development of chronic kidney disease stage 4/5 or death was 21% in the MMF and 22% in the TAC group of patients (p=0.35).. TAC is non-inferior to MMF, when combined with prednisolone, for induction therapy of active LN. With azathioprine maintenance for 5 years, a non-significant trend of higher incidence of renal flares and renal function decline is observed with the TAC regimen.. Hospital Authority Research Ethics Committee Clinical Trial Registry (HARECCTR0500018; Hong Kong) and US ClinicalTrials.gov (NCT00371319).

Topics: Adult; Anti-Inflammatory Agents; Azathioprine; Creatinine; Disease Progression; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Induction Chemotherapy; Kidney Failure, Chronic; Lupus Nephritis; Maintenance Chemotherapy; Male; Middle Aged; Mycophenolic Acid; Prednisolone; Proteinuria; Recurrence; Tacrolimus; Time Factors; Treatment Outcome; Young Adult

To report the 10-year follow-up of the MAINTAIN Nephritis Trial comparing azathioprine (AZA) and mycophenolate mofetil (MMF) as maintenance therapy of proliferative lupus nephritis, and to test different definitions of early response as predictors of long-term renal outcome.. In 2014, data on survival, kidney function, 24 h proteinuria, renal flares and other outcomes were collected for the 105 patients randomised between 2002 and 2006, except in 13 lost to follow-up.. Death (2 and 3 in the AZA and MMF groups, respectively) and end-stage renal disease (1 and 3, respectively) were rare events. Time to renal flare (22 and 19 flares in AZA and MMF groups, respectively) did not differ between AZA and MMF patients. Patients with good long-term renal outcome had a much more stringent early decrease of 24 h proteinuria compared with patients with poor outcome. The positive predictive value of a 24 h proteinuria <0.5 g/day at 3 months, 6 months and 12 months for a good long-term renal outcome was excellent (between 89% and 92%). Inclusion of renal function and urinalysis in the early response criteria did not impact the value of early proteinuria decrease as long-term prognostic marker.. The long-term follow-up data of the MAINTAIN Nephritis Trial do not indicate that MMF is superior to AZA as maintenance therapy in a Caucasian population suffering from proliferative lupus nephritis. Moreover, we confirm the excellent positive predictive value of an early proteinuria decrease for long-term renal outcome.. NCT00204022.

Topics: Adult; Azathioprine; Disease Progression; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Longitudinal Studies; Lupus Nephritis; Maintenance Chemotherapy; Male; Middle Aged; Mycophenolic Acid; Proteinuria; Treatment Outcome

Immunosuppressive therapy plays an important role in patients with high-risk idiopathic membranous nephropathy (IMN), but the therapeutic modality is still controversial.. Corticosteroid combined with oral tacrolimus (TAC, target trough blood concentration of 4-8 ng/mL), intravenous cyclophosphamide (CYC, 750 mg/m(2)/mo, or oral mycophenolate mofetil (MMF, 1.5-2.0 g/d) were randomly administered for 9 months to 90 patients with IMN proved with renal biopsy with severe proteinuria (>8 g/d).. Eighty-six of the 90 patients completed the study. The total remission (TR) rates in the TAC group were significantly higher than those in the CYC group at 1 and 2 months (p < 0.01) and the MMF group at 1-4 months (p < 0.01). The TR rates were 83.3%, 73.3%, and 70.0% in the TAC, CYC, and MMF groups at 9 months (p = 0.457), and there were no significant differences between the three groups from 5 to 9 months. Furthermore, TAC reduced proteinuria and ameliorated hypoalbuminemia more quickly and effectively than CYC and MMF. We observed no severe adverse events in the three groups.. Tacrolimus combined with corticosteroid had tolerable adverse effects and induced the remission of IMN more effectively and more rapidly. This is the first prospective randomized cohort study to compare three different therapies in patients at high risk for IMN. It provides strong evidence for choosing optimal treatment for patients with IMN. The long-term efficacy of this treatment strategy should be investigated further in future studies.

Topics: Adrenal Cortex Hormones; Adult; China; Cyclophosphamide; Drug Therapy, Combination; Female; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Proteinuria; Remission Induction; Tacrolimus; Treatment Outcome

The aim of this study is to evaluate the efficacy and safety of everolimus plus reduced-dose cyclosporine compared with mycophenolate mofetil plus standard-dose cyclosporine 5years after living donor kidney transplantation. Between March 2008 and August 2009, 24 living donor kidney transplantations were enrolled in a 2-year, multicenter, randomized phase 3 study (RAD001A1202 study). 24 recipients were randomly classified into two groups and closely observed for 5years. 13 recipients were administered steroid, reduced-dose cyclosporine, everolimus and basiliximab (EVR group). 11 recipients were administered steroid, standard-dose cyclosporine, mycophenolate mofetil and basiliximab (STD group). Two groups were compared not only in graft function including estimated glomerular filtration rate (eGFR), and proteinuria, but also in adverse events such as de novo donor-specific antibody (DSA) production, rejection, new-onset diabetes, hyperlipidemia, and cytomegalovirus (CMV) infection. No graft loss was identified in 5years. The incidences of acute T cell rejection, de novo DSA production, hyperlipidemia, and new-onset diabetes were similar. eGFR levels throughout the observation periods were similar. Three cases of proteinuria were identified in STD group. One case of proteinuria observed in EVR group was well controlled with angiotensin receptor blocker. Incidence of CMV infection in CMV antibody-positive recipients was significantly lower in EVR group. The safety and efficacy of reduced-dose cyclosporine and everolimus protocol were similar to those of standard-dose cyclosporine and mycophenolate mofetil other than for superior prevention of CMV infection.

Topics: Adult; Cyclosporine; Drug Therapy, Combination; Everolimus; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Humans; Immunosuppressive Agents; Isoantibodies; Kidney Transplantation; Lipid Metabolism; Male; Middle Aged; Mycophenolic Acid; Proteinuria; Retrospective Studies

Previous randomized controlled trials evaluating the efficacy of mycophenolate mofetil (MMF) in patients with immunoglobulin A nephropathy (IgAN) have produced varying results.. Double-blind placebo-controlled randomized controlled trial.. 52 children, adolescents, and adults with biopsy-proven IgAN in 30 centers in the United States and Canada. Entry criteria: age older than 7 to younger than 70 years; urine protein-creatinine ratio (UPCR), ≥0.6g/g (males) or ≥0.8g/g (females); and estimated glomerular filtration rate ≥ 50mL/min/1.73m(2) (≥40mL/min/1.73m(2) if receiving angiotensin-converting enzyme inhibitor). Mean age, 32±12 (SD) years; 62% men; and 73% white.. Lisinopril (or losartan) plus a highly purified omega-3 fatty acid (Omacor [Pronova Biocare]) was given to 94 patients for 3 months; 52 of the patients with persistent UPCR≥0.6g/g (males) and ≥0.8g/g (females) were randomly assigned to MMF or placebo (target dose, 25-36mg/kg/d) in addition to lisinopril/losartan plus Omacor.. Change in UPCR after 6 and 12 months treatment with MMF/placebo and 12 months after the end of treatment.. UPCR measured on 24-hour urine samples. Glomerular filtration rate estimated with the Schwartz (age < 18 years) or Cockcroft-Gault (age ≥ 18 years) formula.. 44 patients completed 6 months of treatment with MMF (n=22) or placebo (n=22). The trial was terminated early at the recommendation of the Data Monitoring Committee because of the lack of benefit. No patient achieved a complete remission (UPCR<0.2g/g). Mean UPCRs at randomization and after 6 months were 1.45 (95% CI, 1.16-1.75) and 1.40 (95% CI, 1.09-1.70) for MMF and 1.41 (95% CI, 1.17-1.65) and 1.58 (95% CI, 1.13-2.04) for placebo, respectively. The mean difference in UPCR change between these groups (MMF minus placebo) was -0.22 (95% CI, -0.75 to 0.31; P=0.4). Adverse events were rare apart from nausea (MMF, 8.7%; placebo, 3.7%); one of these MMF patients withdrew.. Low patient enrollment and short follow-up.. MMF did not reduce proteinuria significantly in patients with IgAN who had persistent proteinuria after lisinopril/losartan plus Omacor.

Topics: Adolescent; Adult; Aged; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Child; Creatinine; Dietary Supplements; Docosahexaenoic Acids; Double-Blind Method; Drug Combinations; Drug Therapy, Combination; Eicosapentaenoic Acid; Female; Glomerular Filtration Rate; Glomerulonephritis, IGA; Humans; Immunosuppressive Agents; Lisinopril; Losartan; Male; Middle Aged; Mycophenolic Acid; Proteinuria; Remission Induction; Treatment Outcome; Young Adult

To explore the efficacy and safety of designed early conversion from calcineurin inhibitor (CNI) to sirolimus (SRL) as major immunosuppressive therapy in renal transplant recipients with stable renal function.. A prospective, open-label and non-randomized control study was performed for 112 renal transplant recipients (3-6 months post-operation) with stable renal function between June 2008 and June 2011. The patients in SRL group (n = 57) switched to sirolimus while those in CNI group (n = 55) continued CNI. The dosing of mycophenolate mofetil and steroids had no change. They were followed up for at least 24 months to evaluate the acute rejection, patient and graft survival, renal function, estimated glomerular filtration rate (eGFR), blood lipids, blood glucose, liver function and urinary protein at 1, 6, 12 and 24 months after inclusion. Adverse events were also recorded.. The serum creatinine of SRL group decreased significantly after conversion ( (89.2 ± 24.7), (87.6 ± 23.8), (86.1 ± 20.4), (86.7 ± 19.7) vs (117.0 ± 16.3) µmol/L, all P < 0.05). CNI group showed no improvement of renal function.SRL group had a significantly higher eGFR than CNI group (P < 0.05). Among 3 cases of acute rejection, there were 2 in SRL group and 1 in CNI group (P > 0.05). Blood lipids in SRL group increased significantly at 1 month after conversion (P < 0.05) and reverted back to average level after intervention (P > 0.05).SRL group had a drop of hemoglobin level within the normal range. Two patients in SRL group developed hypokalemia and another 2 patients had oral ulcer. They all improved after treatment. During follow-ups, 1 case of mild proteinuria was found in SIR group. Three patients were diagnosed with diabetes (1 in SRL group vs 2 in CNI group).. Early conversion from CNI to SRL as major immunosuppressive therapy in renal transplant recipients with stable renal function further improves renal function. There is no higher rate of acute rejection during follow-up.Elevated blood lipids after conversion may be easily controlled. No other adverse events are found.

Topics: Calcineurin Inhibitors; Glomerular Filtration Rate; Graft Survival; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Prospective Studies; Proteinuria; Sirolimus; Treatment Outcome

Clinical trials of therapies for lupus nephritis have used many different primary outcome measures, ranging from complete response to time to end-stage renal disease. The objective of this study was to compare several possible outcome measures, using data from a large, multicenter trial of abatacept in lupus nephritis, to gain insight into which outcome measure, if any, was best able to discern differences among treatment groups.. Study patients received either abatacept or placebo, on a background of mycophenolate mofetil and glucocorticoids. Using data from this trial, the following primary outcome measures at 24 and 52 weeks were compared: complete response rate, major clinical response rate, total response rate (complete plus partial response), improvement in proteinuria, improvement in estimated glomerular filtration rate, and frequency of treatment failure. Time to complete response was also evaluated.. Complete response rate, major clinical response rate, and time to complete response were the measures that best discriminated between the abatacept groups and placebo, and the sensitivities of these 3 measures were comparable. For these measures, sample sizes of 50 patients would have been sufficient to demonstrate a statistically significant difference between treatment and control at 52 weeks. Each of the other measures also discriminated between treatment and control, but much larger group sizes would have been required to determine statistical significance.. The choice of primary outcome measure can substantially influence the ability to detect therapeutic benefit in lupus nephritis trials. This study suggests that complete response rate, major clinical response rate at 52 weeks, and time to complete response may be the most sensitive outcome measures for detecting differences among therapeutic regimens.

Topics: Abatacept; Double-Blind Method; Glomerular Filtration Rate; Glucocorticoids; Humans; Immunoconjugates; Immunosuppressive Agents; Lupus Nephritis; Mycophenolic Acid; Outcome Assessment, Health Care; Proteinuria; Treatment Outcome

Lupus nephritis (LN) is a serious complication of systemic lupus erythematosus (SLE). All current treatment regimens include oral steroids, which are associated with severe adverse events and long-term damage. We have piloted a steroid-avoiding protocol (rituxilup) for the treatment of biopsy-proven active International Society of Nephrology/Renal Pathology Society (ISN/RPS) class III, IV, or class V LN.. We report the findings from the first 50 consecutive patients, treated with 2 doses of rituximab (1 g) and methyl prednisolone (500 mg) on days 1 and 15, and maintenance treatment of mycophenolate mofetil. Patients on maintenance steroids or with life-threatening SLE or requiring dialysis were excluded. Renal remission was defined as serum creatinine no greater than 15% above baseline; complete biochemical remission (CR) was defined as urine protein : creatinine ratio (PCR)<50 mg/mmol or partial remission (PR) if PCR>50 mg/mmol but non-nephrotic and >50% reduction.. A total of 45 (90%) patients achieved CR or PR by a median time of 37 weeks (range 4-200). Overall, 72% (n=36) achieved CR (median time 36 weeks (11-58)) and a further 18% (n=9) achieved persistent PR (median time 32 weeks (19-58)). By 52 weeks, CR and PR had been achieved in 52% (n=26) and 34% (n=17) respectively. In all, 12 relapses occurred in 11 patients, at a median time of 65.1 weeks (20-112) from remission. A total of 6/50 patients had systemic flares. Of the 45 responders, only 2 required >2 weeks of oral steroids. Adverse events were infrequent; 18% were admitted, 10% for an infective episode.. The rituxilup cohort demonstrates that oral steroids can be safely avoided in the treatment of LN. If findings are confirmed, it could mark a step change in the approach to the treatment of LN.

Topics: Adult; Aged; Antibodies, Monoclonal, Murine-Derived; Cohort Studies; Creatine; Drug Substitution; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Lupus Nephritis; Male; Methylprednisolone; Middle Aged; Mycophenolic Acid; Prospective Studies; Proteinuria; Remission Induction; Rituximab; Treatment Outcome; Young Adult

In the FSGS Clinical Trial, 22 cyclosporine-treated and 20 mycophenolate/dexamethasone-treated patients experienced a complete or partial remission after 26 weeks, completed 52 weeks of treatment, and were studied through 78 weeks. Herein, changes in the urine protein/creatinine ratio (UP/C) and estimated GFR (eGFR) throughout the entire study period are defined.. The FSGS Clinical Trial, which was conducted from November 2004 to January 2010, enrolled patients aged 2-40 years, with eGFR ≥40 ml/min per 1.73 m(2) and UP/C >1 mg/mg after ≥4 weeks of corticosteroid therapy. Both groups received lisinopril or losartan throughout the study. UP/C and eGFR were measured at 0, 26, 52, and 78 weeks.. The median UP/C in the cyclosporine- and mycophenolate/dexamethasone-responsive patients fell by 89.8% and 82.7% at 52 weeks; the fall was largely sustained at 78 weeks (74.7% and 80.3%, respectively). The mean eGFR fell by 19.4% in the cyclosporine group and rose by 7.0% in the mycophenolate mofetil/dexamethasone group at 52 weeks, but subsequently rose by 16.4% and fell by 2.6%, respectively, in the two groups from 52 to 78 weeks.. In this subset of responding FSGS patients, the improvement in UP/C after cyclosporine or mycophenolate/dexamethasone treatment was largely sustained for 6 months after therapy. Reduction in eGFR in the cyclosporine group was improved 6 months after cyclosporine was stopped although the levels were lower than baseline in seven patients who entered the study with decreased eGFR.

Topics: Adolescent; Adult; Child; Child, Preschool; Cyclosporine; Dexamethasone; Drug Therapy, Combination; Female; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Function Tests; Male; Mycophenolic Acid; Prospective Studies; Proteinuria; Young Adult

Although mTOR inhibitor use has been associated with proteinuria in kidney transplant recipients, dose dependency and impact on allograft function are unknown. In a post hoc analysis, we compared rates of proteinuria 3 months posttransplant among everolimus (EVR) and mycophenolate (MPA) treatment arms and used a time-dependent model to correlate the risk of proteinuria to EVR trough levels up to 24 months posttransplant. eGFR and graft loss was compared by proteinuria status at 3 months. Of 833 randomized patients, 24%, 36% and 19% of lower exposure EVR (1.5 mg/day), higher exposure EVR (3.0 mg/day) and MPA-treated patients had proteinuria ≥ 300 mg/g Cr at 3 months, respectively. EVR 1.5 was not associated with an increase in risk of proteinuria (HR 1.20; p = 0.19) unlike EVR 3.0 (HR 1.84; p < 0.001) versus MPA. EVR trough levels >8 ng/mL were significantly associated with proteinuria compared to 3-8 ng/mL (HR 1.86; p < 0.001). Those patients with proteinuria at 3 months and those who developed proteinuria thereafter had lower eGFR and higher graft loss at 24 months, regardless of treatment arm. We identify a dose-dependent effect of EVR with the risk of proteinuria; however, its independent impact upon eGFR and graft survival at 2 years was not evident.

Topics: Adult; Cyclosporine; Dose-Response Relationship, Drug; Everolimus; Female; Glomerular Filtration Rate; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Models, Statistical; Mycophenolic Acid; Proteinuria; Risk Factors; Sirolimus; Time Factors; Treatment Outcome

A pooled post-hoc analysis of the phase 3, randomized, placebo-controlled BLISS trials (1684 patients with active systemic lupus erythematosus (SLE)) was performed to evaluate the effect of belimumab on renal parameters in patients with renal involvement at baseline, and to explore whether belimumab offered additional renal benefit to patients receiving mycophenolate mofetil at baseline. In addition to belimumab or placebo, all patients received standard SLE therapy. Patients with severe active lupus nephritis were excluded from the trials. Over 52 weeks, rates of renal flare, renal remission, renal organ disease improvement (assessed by Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index and British Isles Lupus Assessment Group), proteinuria reduction, grade 3/4 proteinuria, and serologic activity favored belimumab, although the between-group differences in most renal outcomes were not significant. Among the 267 patients with renal involvement at baseline, those receiving mycophenolate mofetil or with serologic activity at baseline had greater renal organ disease improvement with belimumab than with placebo. Limitations of this analysis included the small patient numbers and the post-hoc nature of this pooled analysis. The results suggest that belimumab may offer renal benefit in patients with SLE. Further study is warranted in patients with severe active lupus nephritis.

Topics: Antibodies, Monoclonal, Humanized; Asia; Biomarkers; Disease Progression; Drug Therapy, Combination; Europe; Humans; Immunosuppressive Agents; Latin America; Lupus Erythematosus, Systemic; Lupus Nephritis; Mycophenolic Acid; North America; Proteinuria; Remission Induction; Severity of Illness Index; Time Factors; Treatment Outcome

Sirolimus (SRL) is a potent immunosuppressant used in organ transplantation. It is known to decrease vascular endothelial growth factor (VEGF) synthesis, making it an interesting treatment option for transplant patients who develop Kaposi sarcoma or other malignant diseases. Because VEGF plays a key role in glomerular function and vascular remodelling, we determined the effect of SRL on renal VEGF expression.. Using immunohistochemistry and quantitative image analysis, we examined renal VEGF expression in routine kidney biopsies performed at 1 year post-transplant in the CONCEPT study, a prospective randomized study comparing a cyclosporine (CsA)-based regimen to a SRL-based regimen in association with mycophenolate mofetil (MMF).. A total of 74 patients were included in this substudy; 35 were randomized to the CsA group and 39 to the SRL group. Using continuous variables, the mean percentage of glomerular VEGF expression at Week 52 was significantly lower in the SRL group (14.7 ± 13%) compared to CsA group (21.2 ± 14%: P = 0.02). The percentage of glomerular VEGF expression at Week 52 was not influenced by recipient or donor age, gender, renal function, CsA dose, CsA blood level, SRL dose or SRL blood level. It was significantly lower in patients with a proteinuria over versus below 0.5 g/day (11.58 ± 7.9 versus 19.45 ± 15.53; P = 0.036).. There is emerging evidence that the VEGF system can play either a beneficial or a detrimental role depending on the specific pathologic situations. Therefore, modulating the renal VEGF axis by using an SRL-based regimen may influence the evolution of kidney injury associated with renal transplantation.

Topics: Adult; Cyclosporine; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Image Processing, Computer-Assisted; Immunoenzyme Techniques; Immunosuppressive Agents; Kidney Glomerulus; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prognosis; Prospective Studies; Proteinuria; Sirolimus; Vascular Endothelial Growth Factor A

Although the use of aggressive immunosuppression has improved both patient and renal survival of patients with lupus nephritis (LN), the optimal treatment of LN remains challenging. The objective of this study is to assess the efficacy and safety of mycophenolate mofetil (MMF) and tacrolimus compared with intravenous cyclophosphamide (IVC) as induction therapies for active lupus nephritis (ALN).. In this open-label, 24-week prospective study, 60 patients with biopsy-proven ALN (Classes III, IV, V or combination) were randomly assigned to receive MMF, tacrolimus or IVC in combination with corticosteroids. The remission of proteinuria, systemic lupus erythematosus disease active index and adverse events were compared.. The response rates at 24 weeks were 70% (14/20) in the MMF group, 75% (15/20) in the tacrolimus group and 60% (12/20) in the IVC group (P>0.05). The complete remission rates were also similar in the three groups (40, 45 and 30%, respectively; P>0.05). There were more cases of infection in the IVC group (8/20) and the MMF group (8/20) than the tacrolimus group (3/20) and more hyperglycemia in the tacrolimus group (5/20) than the other two groups (2 or 3/20), but the results were not statistically significant among the three groups. Proteinuria decreased and serum albumin increased more quickly in the patients treated with tacrolimus (P=0.0051 and P=0.048).. This pilot study suggests that both MMF and tacrolimus are possible alternatives to IVC as induction therapies for ALN in Chinese patients. Tacrolimus possibly results in a faster resolution of proteinuria and hypoalbuminemia. Further studies are necessary to determine the optimal dosage and duration of the therapies.

Topics: Administration, Oral; Adolescent; Adult; Aged; Cyclophosphamide; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Hypoalbuminemia; Immunosuppressive Agents; Infusions, Intravenous; Lupus Nephritis; Male; Middle Aged; Mycophenolic Acid; Pilot Projects; Prospective Studies; Proteinuria; Remission Induction; Tacrolimus; Treatment Outcome; Young Adult

The safety and efficacy of mycophenolate mofetil (MMF) were evaluated in adolescent patients with systemic lupus erythematosus and active or active/chronic class III-V lupus nephritis. During the 24-week induction phase, patients were randomized to oral MMF (target dose 3.0 g/day) or intravenous cyclophosphamide (IVC) (0.5-1.0 g/m(2)/month), plus prednisone. Response was defined as a decrease in 24-hour urine protein:creatinine ratio (P:Cr) to < 3 in patients with baseline nephrotic range proteinuria, or by ≥ 50% if subnephrotic baseline proteinuria, and stabilization (± 25%) or improvement in serum creatinine. In the 36-month maintenance phase, induction therapy responders were randomized 1:1 to MMF (1.0 g twice daily) or oral azathioprine (AZA) (2 mg/kg/day), plus prednisone. In the induction phase, 10 patients received MMF and 14 received IVC; 15 (62.5%) achieved treatment response (MMF, 7 (70%); IVC, 8/15 (57.1%); p = 0.53, odds ratio (95% confidence interval) 2.0 (0.2, 15.5)). There was a non-statistically significant difference in maintenance of response to MMF (7/8; 87.5%) versus AZA (3/8; 37.5%). Seven patients withdrew (MMF, 2; AZA, 5). During both phases, rates of serious adverse events were similar in both arms. During both phases treatment response with MMF was as effective as the comparator.

Topics: Administration, Oral; Adolescent; Age Factors; Asia; Azathioprine; Biomarkers; Creatinine; Cyclophosphamide; Double-Blind Method; Drug Therapy, Combination; Europe; Female; Humans; Immunosuppressive Agents; Lupus Nephritis; Male; Mycophenolic Acid; Odds Ratio; Prednisone; Prospective Studies; Proteinuria; South America; Time Factors; Treatment Outcome; United States

There is a need to identify clinical characteristics and/or biomarkers that can predict treatment outcome in lupus nephritis. To this end, we utilized data from the Aspreva Lupus Management Study to identify possible baseline and early predictors of renal response to mycophenolate mofetil (MMF) or intravenous (IV) cyclophosphamide (CYC).. Patients with class III-V lupus nephritis were randomized to MMF or IV CYC. We assessed predictors of renal response, including baseline demographic, clinical, laboratory, and histologic characteristics, as well as early clinical and laboratory data, obtained within the first 2 months of therapy. Odds ratios (ORs) and 95% confidence intervals for renal response were calculated for each putative predictor.. Normalization of C3, C4, or both by week 8 was strongly predictive of renal response at week 24 (ORs 2.5, 2.6, and 2.9, respectively; P < 0.05). Reduction in proteinuria by ≥25% by week 8 was predictive of renal response at week 24 (OR 3.2, P < 0.05). Reduction in anti-double-stranded DNA (anti-dsDNA) by week 8 was not predictive of renal response. Only 3 baseline characteristics (C4 level, time since diagnosis of lupus nephritis, and estimated glomerular filtration rate [GFR]) were predictive of renal response; the remaining characteristics (age, age at lupus nephritis onset, time since diagnosis of systemic lupus erythematosus, sex, histopathologic class, anti-dsDNA antibody level, C3 level, level of proteinuria, and use of angiotensin-converting enzyme inhibitors, statins, or hydroxychloroquine) were not.. This study demonstrates that baseline C4 level, time since diagnosis of lupus nephritis, baseline estimated GFR, early normalization of complement, and reduction in proteinuria independently predict renal response to therapy at 6 months.

Topics: Adult; Autoantibodies; Biomarkers; Complement C3; Complement C4; Cyclophosphamide; DNA; Female; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Infusions, Intravenous; Kidney; Logistic Models; Lupus Nephritis; Male; Mycophenolic Acid; Odds Ratio; Predictive Value of Tests; Proteinuria; Pulse Therapy, Drug; San Francisco; Time Factors; Treatment Outcome; Young Adult

Optimal therapy of patients with steroid-resistant primary focal segmental glomerulosclerosis (FSGS) remains controversial. This report describes the initial study design, baseline characteristics, and quality of life of patients enrolled in the FSGS Clinical Trial, a large multicenter randomized study of this glomerulopathy comparing a 12-month regimen of cyclosporine to the combination of mycophenolate mofetil and oral dexamethasone. Patients with age ranging 2-40 years, with an estimated glomerular filtration rate > 40 ml/min per 1.73 m², a first morning urine protein-to-creatinine ratio over one, and resistant to corticosteroids were eligible. The primary outcome was complete or partial remission of proteinuria over 52 weeks after randomization. In all, 192 patients were screened, of whom 138 were randomized for treatment. Ethnic distributions were 53 black, 78 white, and 7 other. By self- or parent-proxy reporting, 26 of the 138 patients were identified as Hispanic. The baseline glomerular filtration rate was 112.4 (76.5, 180.0) ml/min per 1.73 m², and urine protein was 4.0 (2.1, 5.3) g/g. Overall, the quality of life of the patients with FSGS was lower than healthy controls and similar to that of patients with end-stage renal disease. Thus, the impact of FSGS on quality of life is significant and this measurement should be included in all trials.

Topics: Administration, Oral; Adolescent; Adult; Chi-Square Distribution; Child; Child, Preschool; Dexamethasone; Drug Resistance; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Male; Mycophenolic Acid; Prospective Studies; Proteinuria; Pulse Therapy, Drug; Quality of Life; Regression Analysis; Research Design; Surveys and Questionnaires; Time Factors; Treatment Outcome; United States; Young Adult

Class V lupus nephritis (LN) occurs in one-fifth of biopsy-proven cases of systemic lupus erythematosus. To study the effectiveness of treatments in this group of patients, we pooled analysis of two large randomized controlled multicenter trials of patients with diverse ethnic and racial background who had pure class V disease. These patients received mycophenolate mofetil (MMF) or intravenous cyclophosphamide (IVC) as induction therapy for 24 weeks, with percentage change in proteinuria and serum creatinine as end points. Weighted mean differences, pooled odds ratios, and confidence intervals were calculated by using a random-effects model. A total of 84 patients with class V disease were divided into equal groups, each group had comparable entry variables but one received MMF and one received IVC. Within these groups, 33 patients on MMF and 32 patients on IVC completed 24 weeks of treatment. There were no differences between the groups in mean values for the measured end points. Similarly, no difference was found regarding the number of patients who did not complete the study or who died. In patients with nephrotic syndrome, no difference was noted between those treated with MMF and IVC regarding partial remission or change in urine protein. Hence we found that the response to MMF as induction treatment of patients with class V LN appears to be no different from that to IVC.

Topics: Adolescent; Adult; Creatinine; Cyclophosphamide; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Infusions, Intravenous; Lupus Nephritis; Male; Middle Aged; Mycophenolic Acid; Prednisone; Proteinuria; Remission Induction; Renin-Angiotensin System; Young Adult

Treating children with steroid-resistant nephrotic syndrome (SRNS) has been a clinical challenge for pediatricians. We recruited 24 children (18 boys and six girls) with steroid-resistant idiopathic nephrotic syndrome (SRINS) who were <2 years. All patients were administered prednisone 2 mg/kg per day prior to mycophenolate mofetil (MMF). By the end of the eighth week, MMF was initiated at 25-30 mg/kg daily for 6- 12 months. Prednisone dose was reduced stepwise. Biochemical assays were performed every 2 months. Complete remission was achieved in 15 patients, partial remission in six, and no response to MMF was noted in three. With MMF treatment, the levels of urinary protein and serum cholesterol decreased and that of serum albumin increased in a time-dependant manner. We demonstrated the MMF could reduce proteinuria in SRINS children <2 years. Our study suggests that MMF therapy might be an effective strategy for treating SRINS in children <2 years.

Topics: Child, Preschool; Cholesterol; Drug Resistance; Female; Humans; Immunosuppressive Agents; Infant; Male; Mycophenolic Acid; Nephrotic Syndrome; Prednisone; Prospective Studies; Proteinuria; Remission Induction; Serum Albumin; Steroids; Time Factors; Treatment Outcome

Current remission maintenance therapies for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) are limited by partial efficacy and toxicity.. To compare the effects of mycophenolate mofetil with azathioprine on the prevention of relapses in patients with AAV.. Open-label randomized controlled trial, International Mycophenolate Mofetil Protocol to Reduce Outbreaks of Vasculitides (IMPROVE), to test the hypothesis that mycophenolate mofetil is more effective than azathioprine for preventing relapses in AAV. The trial was conducted at 42 centers in 11 European countries between April 2002 and January 2009 (42-month study). Eligible patients had newly diagnosed AAV (Wegener granulomatosis or microscopic polyangiitis) and were aged 18 to 75 years at diagnosis.. Patients were randomly assigned to azathioprine (starting at 2 mg/kg/d) or mycophenolate mofetil (starting at 2000 mg/d) after induction of remission with cyclophosphamide and prednisolone.. The primary end point was relapse-free survival, which was assessed using a Cox proportional hazards model. The secondary end points were Vasculitis Damage Index, estimated glomerular filtration rate, and proteinuria.. A total of 156 patients were assigned to azathioprine (n = 80) or mycophenolate mofetil (n = 76) and were followed up for a median of 39 months (interquartile range, 0.66-53.6 months). All patients were retained in the analysis by intention to treat. Relapses were more common in the mycophenolate mofetil group (42/76 patients) compared with the azathioprine group (30/80 patients), with an unadjusted hazard ratio (HR) for mycophenolate mofetil of 1.69 (95% confidence interval [CI], 1.06-2.70; P = .03). Severe adverse events did not differ significantly between groups. There were 22 severe adverse events in 13 patients (16%) in the azathioprine group and there were 8 severe adverse events in 8 patients (7.5%) in the mycophenolate mofetil group (HR, 0.53 [95% CI, 0.23-1.18]; P = .12). The secondary outcomes of Vasculitis Damage Index, estimated glomerular filtration rate, and proteinuria did not differ significantly between groups.. Among patients with AAV, mycophenolate mofetil was less effective than azathioprine for maintaining disease remission. Both treatments had similar adverse event rates.. clinicaltrials.gov Identifier: NCT00307645.

Topics: Adult; Aged; Antirheumatic Agents; Azathioprine; Cyclophosphamide; Female; Glomerular Filtration Rate; Granulomatosis with Polyangiitis; Humans; Immunosuppressive Agents; Male; Microscopic Polyangiitis; Middle Aged; Mycophenolic Acid; Prednisolone; Proteinuria; Secondary Prevention

To evaluate and describe the pharmacokinetics of mycophenolic acid and its metabolite, mycophenolic acid glucuronide (MPAG), in patients with lupus nephritis, and to determine the effects of clinical parameters (urinary protein excretion as measured by the urinary protein:creatinine ratio, serum albumin level, and creatinine clearance) and demographic variables (age, race, sex) on the pharmacokinetics of total and unbound mycophenolic acid and MPAG.. Pharmacokinetic analysis.. University-affiliated general clinical research center.. Eighteen patients with biopsy-confirmed lupus nephritis who were receiving maintenance therapy with mycophenolic acid for at least 2 weeks.. Plasma and urine samples were collected for 24 hours and were assayed by high-performance liquid chromatography with ultraviolet detection.. Time to maximum concentration was variable (0.5-8 hrs). Mean +/- SD fraction of unbound mycophenolic acid was 2.6 +/- 1.9%, and oral clearance (Cl/F) was about 2-fold higher (343 +/- 200 ml/min) than previously reported. Multiple regression analysis showed that Cl/F of mycophenolic acid was predicted by creatinine clearance and serum albumin level: ln Cl/F = 5.358 + 0.0092 (creatinine clearance) - 0.078 (ranked albumin), R(2)=51.1%, p=0.0195. Patients with urinary protein excretion of 1 g/day or higher had lower minimum (trough) concentrations and area under the concentration-time curve (AUC(0-12)) profiles and higher Cl/F values compared with patients with urinary protein excretion of less than 1 g/day. Patients with serum albumin levels less than 4 g/dl had higher mycophenolic acid unbound clearance and MPAG renal clearance from 0-12 hours versus those with serum albumin levels of 4 g/dl or greater. Recycling AUC (AUC(6-12)), as well as sex and age (both equally), predicted renal clearance of MPAG.. Both creatinine clearance and serum albumin level were identified as primary contributors to mycophenolic acid exposure and should be considered when evaluating dosages. The results of future studies should clarify the interactions of other variables on drug exposure and treatment responses. Clinicians need to be mindful of clinical changes that occur throughout the course of lupus nephritis in order to maintain efficacy and reduce toxicity from mycophenolic acid therapy.

Topics: Adult; Age Factors; Creatinine; Enzyme Inhibitors; Ethnicity; Female; Glucuronides; Humans; Lupus Nephritis; Male; Mycophenolic Acid; Proteinuria; Serum Albumin; Sex Factors

Calcineurin inhibitors (CNIs) induce remission of proteinuria in most nephrotic patients with membranous glomerulonephropathy (MGN). However, 60% of patients become treatment dependent and are at risk of chronic nephrotoxicity. The aim of this study was to evaluate the efficacy of rituximab in patients with long-term dependence on CNIs.. Thirteen patients with MGN, normal renal function, and proven dependence on CNIs, despite previous treatment with other immunosuppressant drugs, received a single trial of four weekly doses of rituximab (375 mg/m(2)). Outcome measures were the percentage of patients with CNI withdrawal and no evidence of relapse and the percentage of patients with complete or partial remission 30 mo after CNI withdrawal.. After rituximab, proteinuria decreased significantly (2.5 +/- 0,76 basal versus 0.85 +/- 0.17 at 6 mo; P = .0003). CNIs and other immunosuppressant drugs could be withdrawn in all patients with no evidence of relapse. After CNI withdrawal, GFR increased significantly (90.3 +/- 15 basal to 106.4 +/- 20 at 3 mo with a mean increase of 15.3% [range 0-20]). Three patients suffered a relapse of nephrotic proteinuria 19, 23, and 28 mo after rituximab treatment; all were successfully treated with a second course of rituximab. At 30 mo, all patients were in remission.. In patients with MGN with long-term CNI dependence, rituximab can be an effective tool to overcome dependence on CNI, thus avoiding the risk of nephrotoxicity related to the chronic exposure to these drugs.

Topics: Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Biopsy; Calcineurin Inhibitors; Enzyme Inhibitors; Female; Follow-Up Studies; Glomerulonephritis, Membranous; Humans; Immunologic Factors; Kidney; Male; Middle Aged; Mycophenolic Acid; Pilot Projects; Proteinuria; Remission Induction; Rituximab; Substance Withdrawal Syndrome

Treatment of patients with membranous glomerulonephritis (MGN) is controversial because of the lack of clear benefit of the immunosuppressive regimens on patient or renal survival. The objective of this study is to evaluate the efficacy and safety of mycophenolate mofetil (MMF) for patients with MGN.. 1-year prospective, randomized, and controlled clinical trial.. 36 patients with biopsy-proven idiopathic MGN and nephrotic syndrome.. 19 patients received MMF (2 g/d) for 12 months and 17 patients were in the control group. All patients had the same conservative treatment based on renin-angiotensin blockers, statins, low-salt and low-protein diet, and diuretics in case of edema.. End points were the mean proteinuria over creatinuria ratio in mg/g throughout the study and numbers of complete and partial remissions at 1 year (month 12). Data were analyzed on an intention-to-treat analysis.. Mean proteinuria over creatinuria ratio was stable in both groups throughout the study (P = 0.1). Mean proteinuria over creatinuria ratio was 4,690 +/- 2,212 mg/g in the MMF group and 6,548 +/- 4,601 mg/g in the control group (95% confidence interval of the difference, -619 to +4,247; P = 0.1). Remission was complete in 3 patients (1 in the MMF group, 2 in the control group; P = 0.5) and partial in 11 patients (6 in the MMF group, 5 in the control group; P = 0.9). The probability of complete or partial remission did not differ between the 2 groups after 12 months (relative risk, 0.92; 95% confidence interval, 0.48 to 1.75; P = 0.7). Kidney function was stable in the 2 groups according to estimated glomerular filtration rate and serum creatinine level.. The small number of patients and short follow-up prevent generalizations.. A 12-month regimen of MMF did not decrease mean proteinuria over creatinuria ratio or increase partial and complete remissions. Serious adverse effects were observed in 4 patients (20%) receiving MMF.

Topics: Adult; Aged; Creatinine; Dose-Response Relationship, Drug; Female; Glomerular Filtration Rate; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Outcome Assessment, Health Care; Prospective Studies; Proteinuria; Treatment Outcome

Sirolimus (SRL) is a potent immunosuppressive drug used to prevent acute allograft rejection after renal transplantation. Nevertheless, the occurrence of proteinuria has recently been recognized among patients on SRL-based therapy. The aim of this study was to investigate the therapeutic effects of Tripterygium wilfordii Hook F. (T II) on proteinuria associated with SRL in renal transplant recipients. According to accepting T II, 36 recipients were divided into 2 groups: T II group (n = 21) and valsartan group (n = 15). The T II group was administered 1 mg/kg/d, and the valsartan group, 80 mg twice per day for 12 months. Efficiency was then evaluated. Complete remission: proteinuria decreased by >50%; partial remission: proteinuria decreased by 20% to 50%; ineffective: proteinuria decreased by <20%. Upon 12-month follow-up, the total effective rates in the T II group and the valsartan group were 95.2% and 86.7% (P < .05), respectively. Twenty of 21 patients with proteinuria in the T II group were negative at 3-month follow-up with disappearance of edema. There were some adverse events that had greater incidence rates in the valsartan group compared with the T II group, such as hyperkalemia (26.7% vs 4.8%). We concluded that the application of T II markedly reduced proteinuria associated with SRL in renal transplant patients.

Topics: Adult; Antihypertensive Agents; China; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Plant Extracts; Proteinuria; Sirolimus; Tetrazoles; Tripterygium; Valine; Valsartan; Young Adult

Studies of mycophenolate mofetil (MMF) in primary glomerulonephritis have varied in their inclusion criteria, regimen and follow-up compromising assessments of efficacy and optimal dose.. This multicentre study analysed the safety and efficacy of MMF monotherapy in a large cohort with primary glomerulonephritis that was resistant to other conventional therapies. A total of 98 patients with biopsy-proven primary glomerulonephritis resistant to other drugs received MMF monotherapy for 1 year. Primary outcome measures were urinary protein excretion and the number of patients with complete or partial remission of proteinuria. Secondary analyses were time to remission and changes in the slope of creatinine clearance.. Fifty-four percent of the patients achieved either complete or partial remission of proteinuria with no significant differences between glomerulonephritis types. Median (range) dose of MMF was 2 g/day (1.5-2 g/day) Mean (SD) treatment time to remission was 141.5 (+/-61.1) days with no significant differences between glomerulonephritis types. Serum albumin increased (P<0.01), whereas proteinuria (P<0.01) serum LDL-cholesterol (P<0.01) and mean blood pressure (P<0.05) decreased post-treatment. No significant changes were observed in glomerular filtration rate (GFR), serum creatinine or slopes of GFR. The reduction of urinary protein excretion was significantly higher in patients with basal nephrotic proteinuria and preserved renal function; it did not arise from an increased dose of angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists, since, among responders, mean blood pressure significantly decreased and the number of anti-hypertensive drugs could be reduced.. MMF monotherapy causes a moderate decrease in proteinuria in >50% of the patients who do not have other treatment options. The response to therapy is largely influenced by a preserved renal function and requires sustained MMF treatment.

Topics: Adult; Blood Pressure; Creatinine; Dose-Response Relationship, Drug; Female; Glomerular Filtration Rate; Glomerulonephritis; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Proteinuria; Salvage Therapy; Treatment Outcome

New immunosuppressive agents are being actively researched to avoid complications of chronic allograft nephropathy (CAN), calcineurin inhibitor (CNI) nephrotoxicity, and posttransplantation cancer. The family of mTOR inhibitors offers a unique immunosuppressive opportunity to avoid CNI toxicity and reduce the incidence of malignancy. Nevertheless, increasing data have demonstrated that sirolimus (SRL), the first mTOR introduced in the treatment of solid organ transplant recipients, induces proteinuria, an adverse event that could produce deterioration of long-term renal function. In this short-term study of patients followed for 1 to 16 months, we examined changes in renal function and proteinuria among renal transplant recipients converted from a CNI-based regimen to an everolimus (EVL)-based one, a recently introduced mTOR inhibitor. Our data showed that renal function can be optimized after conversion to EVL by up to 42% in recipients showing CAN grade 1 or 2, or CNI nephrotoxicity. Importantly, patients who improved their creatinine clearance did not show increased proteinuria measured in a voided specimen as the ratio of urinary protein and creatinine concentration (P/C). These results, if confirmed with long-term follow-up and a larger number of patients, would allow us to consider EVL as a promising agent for maintenance immunosuppressive regimens in kidney transplantation.

Topics: Aged; Antibodies, Monoclonal; Antilymphocyte Serum; Azathioprine; Basiliximab; Calcineurin Inhibitors; Cyclosporine; Drug Therapy, Combination; Everolimus; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Proteinuria; Recombinant Fusion Proteins; Sirolimus

The contribution of mammalian target of rapamycin (mTOR) inhibitors to proteinuria is controversial. The aim was to analyse proteinuria in suboptimal kidney calcineurin inhibitor-(CNI) free de novo immunosuppression.. All patients from our centre with donors >60 years and CNI-free treatment were included (n = 108). Patients were divided into two groups: (i) SRL group: sirolimus (SRL) + prednisone + mycophenolate mofetil (MMF) + antiCD25; (ii) MMF group: prednisone + MMF w/ or w/o antiCD25 (n = 75). Follow-up was 12 months.. Donors were slightly younger in the SRL group (68 vs 71 years; P < 0.05), receptor age (67 vs 65 years) was not significantly different. Patient survival in the MMF group was 88 vs 94% in the SRL group, however, these differences did not reach statistical significance. One-year graft survival censored for death was 83% in the MMF group and 94% in the SRL group. Acute rejection rate was 45% in the MMF and 15% in the SRL group (P < 0.01). The incidence of CNI introduction was higher in the MMF-group (35 vs 5; P < 0.05). The intention-to-treat analysis revealed significant differences of proteinuria [SRL vs MMF at 12 months: 461 (163-6988) vs 270 (53-3029) mg/day], which did not exist in the on-therapy (OT) analysis [SRL vs MMF at 12 months: 357 (199-1428) vs 279 (53-3029) mg/day]. New onset nephrotic range proteinuria seemed to occur slightly more frequently in SRL patients (3/33 vs 1/75; P = 0.049), however, all four cases occurred in a context of recurrent disease, or previous drug-independent damage or non-adherence. All of these patients were converted to CNI.. SRL-based compared with MMF-based treatment in kidney transplantation with advanced age donors is associated with an acceptable outcome, however, with increased proteinuria in the intention-to-treat analysis. A large subgroup of the patients in the MMF group experienced acute rejection and required conversion to CNI.

Topics: Aged; Calcineurin Inhibitors; Graft Survival; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Interleukin-2 Receptor alpha Subunit; Kidney Transplantation; Middle Aged; Mycophenolic Acid; Prednisone; Protein Kinases; Proteinuria; Sirolimus; Time Factors; TOR Serine-Threonine Kinases

The Mycophenolate Steroids Sparing (MYSS) study found that in renal transplant recipients who were on immunosuppressive therapy with the cyclosporine microemulsion Neoral, mycophenolate mofetil (MMF) was not better than azathioprine in preventing acute rejection at 21 mo after transplantation and was 15 times more expensive. The MYSS Follow-up Study, an extension of MYSS, was aimed at comparing long-term outcome of 248 MYSS patients according to their original randomization to MMF (1 g twice daily) or azathioprine (75 to 100 mg/d). Primary outcome was estimated GFR at 5 yr after transplantation. Mean 5-yr GFR difference between azathioprine and mycophenolate was 4.67 ml/min per 1.73 m(2) (95% confidence interval [CI] -0.43 to 9.77 ml/min per 1.73 m(2); P = 0.07). GFR from month 6 (mean +/- SEM: 54.3 +/- 1.6 versus 53.9 +/- 1.5 ml/min per 1.73 m(2); P = 0.83) to month 72 after transplantation (49.5 +/- 2.2 versus 47.3 +/- 2.4 ml/min per 1.73 m(2); P = 0.50); GFR slopes (mean +/- SEM: -1.10 +/- 0.56 versus -1.23 +/- 0.31 ml/min per 1.73 m(2) per year; P = 0.83); and 72-mo patient mortality (4.0 versus 4.0% [P = 0.95]; HR 0.96; 95% CI 0.28 to 3.31; P = 0.95), graft loss (6.8 versus 6.1% [P = 0.82]; HR 0.89; 95% CI 0.32 to 2.46; P = 0.83), incidence of persistent proteinuria (25.0 versus 27.4%; P = 0.72), late (>6 mo after transplantation) rejections (25.3 versus 21.2%; P = 0.53), and adverse events were similar on azathioprine (n = 124) and MMF (n = 124), respectively. Outcomes in the two groups were comparable also among patients with or without steroid therapy, considered separately. In kidney transplantation, the long-term risk/benefit profile of MMF and azathioprine therapy in combination with cyclosporine Neoral is similar. In view of the cost, standard immunosuppression regimens for kidney transplantation should perhaps include azathioprine rather than MMF.

Topics: Adult; Azathioprine; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Predictive Value of Tests; Proteinuria; Risk Assessment; Transplantation, Homologous; Treatment Outcome

The management of steroid-resistant glomerulopathies remains a clinical problem. In this trial, we report a clinical observation of 43 patients treated with mycophenolate mofetil (MMF) for steroid-resistant glomerulopathies.. All patients underwent renal biopsies, and immunofluorescence and light microscopy examinations were conducted in all cases. All patients had been treated with prednisone at a dose of 1 mg/kg per day for at least 8 weeks. Of the 43 patients, 16 were treated with cyclophosphamide and five were treated with cyclosporine A before MMF started. The primary study outcomes were the change in the urinary protein excretion, serum creatinine, comparing the levels at the start of MMF treatment with those at the end of the MMF treatment period. Changes in renal function were also estimated with Modification of Diet in Renal Failure calculation. Wilcoxon signed-ranks test was used as appropriate to compare data from the start with data at the end of the treatment period.. The primary glomerular diseases represented included membranoproliferative glomerulonephritis in 23.2%, membranous glomerulonephritis in 18.6%, IgA nephropathy in 13.9%, focal segmental glomerulosclerosis in 9.3%, lupus nephritis (systemic lupus erythematosus) in 25.6% and pauci-immune glomerulopathy in 9.3% of patients. The mean follow-up time was 28.9+/-12 months. Before MMF treatment, 16 patients (37%) had nephrotic range proteinuria and 11 (26%) had renal insufficiency. The urinary protein before MMF treatment was 3.3+/-2.6 g/dL (0.6-9.6) and decreased significantly to 0.87+/-1.1 g/dL (0-5.5) at the end of the MMF treatment period (P=0.02). During treatment, complete remission was seen in 27 patients, partial remission in 10 patients and MMF failure in six patients. The serum creatinine level decreased significantly from 1.29+/-0.55 mg/dL (0.6-3.0) to 1.14+/-0.38 mg/dL (0.5-2.4) post MMF therapy (P=0.046). Using the four-variable Modification of Diet in Renal Failure formula, the glomerular filtration rate increased from 71.5+/-28 mL/min per 1.73 m2 to 78.1+/-27 mL/min per 1.73 m2 (P=0.021). Renal insufficiency resolved in seven of the 11 (63.6%) patients with renal insufficiency initially, two with membranoproliferative glomerulonephritis, two with membranous glomerulonephritis, one with focal segmental glomerulosclerosis, four with pauci-immune glomerulopathy, two with systemic lupus erythematosus nephritis, and in two patients de novo renal insufficiency developed.. In general, MMF was well tolerated, and most of the patients achieved remission and improvement of renal functions. MMF treatment appeared to offer benefits to problematic patients refractory to conventional therapies for glomerulopathies.

Topics: Adolescent; Adult; Creatine; Female; Glomerular Filtration Rate; Glomerulonephritis; Humans; Kidney Glomerulus; Male; Microscopy, Fluorescence; Middle Aged; Mycophenolic Acid; Prednisone; Proteinuria; Statistics, Nonparametric; Treatment Outcome

Membranous nephropathy is a common cause of nephrotic syndrome (NS) in adults. Its treatment is still under debate.. We report our experience in a pilot study using initially low doses of steroids and tacrolimus (Tac). After 3 months of treatment, mycophenolate mofetil (MMF) was added if the proteinuria was higher than 1 g/day.. In accordance with this standard, 21 patients entered the study. A proteinuria level lower than 1 g/day was reached at month 3 of therapy with steroids and Tac in 11 patients. These patients continued this treatment for 12 months. MMF was added in nine cases after the third month and triple therapy was maintained for 12 more months. Two patients were withdrawn because of side effects. At the end of the treatment, remission of the NS was present in 15 out of all the patients (71.4%). Remission of the NS was complete in eight (53.3%) patients and partial in seven (46.7%) others. The remaining four patients did not respond. There were no significant changes in renal function. At a mean time of 23.1 months after treatment was discontinued, 11 (73.3%) patients had relapsed.. In this trial, treatment with tacrolimus showed a good efficacy but a high relapse rate when it was discontinued.

Topics: Adrenal Cortex Hormones; Adult; Aged; Albuminuria; Biopsy; Cholesterol; Creatinine; Drug Therapy, Combination; Female; Glomerulonephritis, Membranous; Humans; Male; Middle Aged; Mycophenolic Acid; Proteinuria; Tacrolimus

Cyclophosphamide can decrease proteinuria and improve renal function in patients with idiopathic membranous nephropathy, but has a high risk of side effects. We studied whether mycophenolate mofetil (MMF) could be a reasonable alternative with fewer side effects.. Clinical trial with historic controls.. 32 cases and 32 controls with idiopathic membranous nephropathy and renal insufficiency at multiple centers. For comparison, we selected matched historic controls treated with cyclophosphamide.. MMF, 1 g twice daily, for 12 months versus cyclophosphamide, 1.5 mg/kg/d, for 12 months. Both groups also received intermittent methylprednisolone and alternate-day prednisone.. Serum creatinine, proteinuria, and side effects during and after treatment.. Median follow-up was 23 months (range, 11 to 46 months). Median serum creatinine levels were 1.8 mg/dL (159 micromol/L) in both groups at baseline and 1.4 mg/dL (124 micromol/L) in the MMF group versus 1.3 mg/dL (115 micromol/L) in the cyclophosphamide group at 12 months (P = 0.4). Proteinuria values at baseline and 12 months were protein of 8.40 and 1.41 g/d in the MMF group versus 9.19 and 1.13 g/d in the cyclophosphamide group (P = 0.5 at 12 months), respectively. Cumulative incidences of remission of proteinuria at 12 months were 66% in the MMF group versus 72% in the cyclophosphamide group (P = 0.3). Five patients (16%) in the MMF group versus none in the cyclophosphamide group had disease that did not respond to therapy (P = 0.05). Twelve patients (38%) experienced a relapse and 9 patients (31%) were re-treated in the MMF group compared with 4 (13%) and 2 patients (6%) in the cyclophosphamide group (P < 0.01 and P = 0.024, respectively). Side effects occurred in 24 patients (75%) in the MMF group and 22 patients (69%) in the cyclophosphamide group (P = 0.6).. Nonrandomized control group, short duration of follow-up.. A 12-month course of MMF decreased proteinuria and improved renal function in the majority of patients, but did not appear as effective or better tolerated than cyclophosphamide. Long-term data and randomized controlled trials are needed to ascertain the efficacy of MMF in patients with idiopathic membranous nephropathy.

Topics: Adult; Aged; Cohort Studies; Cyclophosphamide; Female; Follow-Up Studies; Glomerulonephritis, Membranous; Humans; Male; Middle Aged; Mycophenolic Acid; Proteinuria

The presence of renal noninflammatory necrotizing vasculopathy (NNV) is often associated with a severe form of lupus nephritis (LN), which is unresponsive to standard therapy. We conducted a 6-month randomized, prospective, open-label trial comparing mycophenolate mofetil (MMF) (1.5-2.0 g/day) with monthly i.v. cyclophosphamide (CTX) (0.75-1.0 g/m2) as induction therapy for class IV LN with NNV. The primary and second end points were complete remission (CR) and partial remission (PR), respectively. Of 20 patients recruited, nine were randomly assigned to MMF and 11 to CTX. The baseline characteristics between groups were not significant. CR was achieved in four patients (44.4%) receiving MMF and in none of the patients receiving CTX (P = 0.026). PR was achieved in two patients (22.2%) in the MMF group and three patients (27.2%) in the CTX group. The total remission rate (CR + PR) in the MMF and CTX group was 66.6 and 27.2%, respectively (P = 0.17). MMF was more effective than i.v. CTX in reducing proteinuria and haematuria. Adverse events were significantly less frequent with MMF than with CTX (P = 0.028). MMF was superior to i.v. CTX in inducing CR of LN with NNV and had a more favourable safety profile.

Topics: Adolescent; Adult; Cyclophosphamide; Dose-Response Relationship, Drug; Drug Therapy, Combination; Follow-Up Studies; Glucocorticoids; Hematuria; Humans; Immunosuppressive Agents; Infusions, Intravenous; Lupus Nephritis; Middle Aged; Mycophenolic Acid; Prospective Studies; Proteinuria; Remission Induction; Vascular Diseases

Treatment of primary glomerular diseases may be unsuccessful or have potential toxicities. Mycophenolate mofetil (MMF) is a new, relatively non-toxic drug. It has been introduced as an immunosuppressive drug, but it also has effects on non-immune cells (vascular smooth muscle cells, fibrocytes). Therefore, we evaluated the use of MMF for the treatment of glomerular diseases at different stages of the disease.. The daily dosage of MMF was 2 for the first 6 months and 1.5 g for a further 18 months, combined with steroids. The follow-up period was two years.. 18 patients with lupus nephritis were treated. Patients with a high histological activity index showed a significant decrease of serum creatinine (p < 0.05) and proteinuria (p < 0.01), while patients with a high chronicity index showed only a decrease of proteinuria (p < 0.05). 15 patients with membranous nephropathy were treated. They showed stable renal function and a significant decrease of proteinuria (p < 0.05). Complete remission was achieved only in patients with MMF as a first choice drug. 4 patients with focal segmental glomerulosclerosis did not show any significant decrease of proteinuria, while the nephrotic syndrome in minimal change nephropathy (3 patients) showed a complete recovery. Partial improvement of the nephrotic syndrome was noted in 5 patients with membranoproliferative glomerulonephritis and in 4 patients with crescentic glomerulonephritis. Patients with crescentic glomerulonephritis also presented a significant decrease of serum creatinine (p < 0,05). MMF in 3 patients with IgA nephropathy grade I showed a significant improvement of the nephrotic syndrome. In grade III (5 patients) the response was partial.. We can conclude that MMF in our patients showed both actions, as an immunosuppressive drug in the early stages of the disease, and as an anti-fibrotic agent in the chronic phase of the disease.

Topics: Adult; Female; Glomerulonephritis; Humans; Immunosuppressive Agents; Kidney; Male; Middle Aged; Mycophenolic Acid; Proteinuria

Mycophenolate mofetil (MMF) significantly reduces proteinuria in experimental model of human membranous nephropathy (Heymann nephritis). Twenty consecutive SLE patients with persistent isolated severe proteinuria and/or proteinuric flare were studied for 18 months of MMF therapy. All of them presented stable renal function and 12 had biopsy proven membranous glomerulonephritis (WHO class V). The starting daily dose for MMF was 1.5 g to a maximum of 3 g. Patients were divided into: partial response, >or=50% decrease of baseline proteinuria; complete response, normal proteinuria levels (less than 0.3 g/24 h); flare, increase of at least 50% of the mean baseline proteinuria. All 20 SLE patients (100%) presented a 50% reduction of baseline proteinuria which was achieved in 8.2+/-3.3 months of MMF therapy, at a mean daily dose of 2.3+/-0.5 g. A significant decrease in 24-h protein excretion was observed compared to entry (3.47+/-1.26 vs. 1.33+/-0.67 g, P<0.0001) as well as a correspondent increase of serum albumin (3.2+/-0.4 vs. 3.7+/-0.4 mg/dl, P=0.02) and reduction of prednisone dose (33.7+/-20.0 to 18.6+/-14.1 mg/day, P=0.01). Complete response was observed in 11 SLE patients (55%) in 12.2+/-3.0 months of therapy with a significant decrease in proteinuria (P<0.0001), prednisone dose (P<0.0001) and an increase of serum albumin (P=0.003). Interestingly, initial proteinuria or serum albumin levels did not identify patients with complete response and those with partial response at the end of the study (P=0.543 and 0.657, respectively). Our pilot prospective study suggests that MMF appears to be effective in reducing severe persistent proteinuria in lupus glomerulonephritis, even in patients unresponsive to other immunosuppressive treatments.

Topics: Adult; Female; Humans; Immunosuppressive Agents; Lupus Nephritis; Male; Mycophenolic Acid; Proteinuria; Treatment Outcome

Children with frequently relapsing nephrotic syndrome (FRNS) often develop adverse effects from prednisone. Attempts to induce long-term remission in such patients have had varying levels of success. In this multicenter, prospective, open-label study, 14 centers enrolled 33 patients with FRNS, all of whom were in remission at the time of entry. Six of the patients were steroid dependent. The patients received mycophenolate mofetil (MMF) 600 mg/m(2) twice daily (maximum 1 g twice daily) for 6 mo. A tapering dosage of alternate-day prednisone was given to each patient during the first 16 wk of MMF therapy. Patients were monitored for relapses of NS during and after MMF therapy. Treatment failure was defined as a relapse of NS. The patients had the following features at study entry: Age 6.8 +/- 2.7 yr (range 2 to 15 yr); 56% male, 44% female; and 50% white; 25% black, and 25% other. Estimated GFR at entry was 138 +/- 42 ml/min per 1.73 m(2). Twenty-four (75%) of 32 patients stayed in remission throughout the 6 mo of MMF therapy. The relapse rate in these patients improved from one episode every 2 mo before MMF to one every 14.7 mo after MMF. Eight patients stayed in remission during the post-MMF period, for periods of 18 to 30 mo, whereas 16 relapsed after stopping MMF. Eight (25%) of 32 patients relapsed while taking MMF. It is concluded that MMF is effective for maintaining remission in patients who have FRNS and receive treatment for at least 6 mo and is associated with a low incidence of adverse events.

Topics: Adolescent; Adult; Child; Child, Preschool; Drug Administration Schedule; Humans; Immunosuppressive Agents; Monitoring, Physiologic; Mycophenolic Acid; Nephrotic Syndrome; Patient Selection; Proteinuria; Recurrence

Mycophenolate mofetil (MMF) is increasingly used to treat primary glomerulopathies. Its effectiveness in IgA nephropathy (IgAN) remains unclear.. Forty IgAN patients with persistent proteinuria (>1 g/24 hours) despite conventional treatment with blockers of the renin-angiotensin system were randomized to receive MMF for 24 weeks (group 1) or continue conventional therapy (group 2), and followed for 72 weeks. The primary end point was reduction of proteinuria by 50% or more over entry level.. Sixteen patients (80%) in group 1 versus six patients (30%) in group 2 reached the primary end point (P= 0.0019). Time-averaged change in proteinuria showed a significant decline in group 1, while control subjects displayed a modest rise (P= 0.003). By 72 weeks, the mean proteinuria was 62.0 +/- 7.7% (P= 0.003) and 120.5 +/- 14.1% (P= 0.351) that of the corresponding baseline value in group 1 and group 2, respectively. There was concomitant increase in serum albumin and decrease in serum IgA levels in group 1 but not group 2 patients. Baseline histologic grades, blood pressure control, and the rates of change in serum creatinine and creatinine clearance were not different between the two groups. Normalization in binding of polymeric IgA to cultured mesangial cells and serum interleukin-6 (IL-6) levels, which sustained to study end, was observed in group 1 but not group 2 subjects.. In selected patients with IgAN, MMF is effective in lowering proteinuria and ameliorating some of the putative pathogenetic abnormalities.

Topics: Adult; Blood Pressure; Female; Glomerulonephritis, IGA; Humans; Immunoglobulin A; Immunosuppressive Agents; Lymphocyte Count; Male; Middle Aged; Mycophenolic Acid; Proteinuria; Sodium; Treatment Outcome

IgAN is the most common type of glomerulonephritis in the world. Between 15 and 40 percent of adults and children diagnosed with IgAN eventually progress to ESRD. Despite the need for effective treatment strategies, very few RCTs for IgAN have been performed. The most effective therapies for IgAN appear to be corticosteroids, ACEi, and FOS that contain a high concentration of omega 3 fatty acids. While ACEi and FOS are generally well tolerated with minimal side effects, the use of high dose steroids over a long course of therapy is often associated with significant morbidity.. The objective of the study is to test the hypothesis that treatment with the immunosuppressive agent, MMF, will lead to significant and sustained improvement in urinary protein excretion in patients with IgAN who have been pre-treated (and continue to be treated) with ACEi and FOS compared to a placebo control group of patients receiving comparable doses of ACEi and FOS without MMF.. After a three month treatment period with the ACEi, lisinopril and the FOS, Omacor, 100 (2 x 50) patients with IgAN and a urinary P/C ratio > or = 0.6 (males) and > or = 0.8 (females) and an estGFR > or = 40 ml/min/1.73 m2 will be randomized to treatment with either MMF or placebo for one year. All patients will be followed off study drug for a second year, but will continue treatment with lisinopril and Omacor for the two year duration of the study. The primary outcome measure of change in urine P/C ratio will be assessed at the end of years one and two.

Topics: Angiotensin-Converting Enzyme Inhibitors; Docosahexaenoic Acids; Drug Combinations; Drug Therapy, Combination; Eicosapentaenoic Acid; Female; Glomerular Filtration Rate; Glomerulonephritis, IGA; Humans; Immunosuppressive Agents; Lisinopril; Male; Mycophenolic Acid; Proteinuria; Research Design; Treatment Outcome

To study the effect of mycophenolate mofetil (Cell Cept) in treating patients with various types of chronic glomerulonephritis and other immune nephropathies.. Between 2000 and 2003 we treated 35 patients (18 women, 17 men) with Cell Cept (La Roche). In 32 patients the diagnosis was confirmed by kidney biopsy (immunofluorescence, light and electron microscopy).. Treatment with Cell Cept was very successful in 22 of the patients in the study (62.86%). Proteinuria was significantly reduced and firmly maintained well below 0.5 g/l; serum protein levels were elevated to normal values, the edemas disappeared. In 12 patients the drug had a good effect: there was a significant reduction of proteins in the urea within 1.2 - 2.0 g/l, an increase of total protein and albumins in plasma but after three months of treatment. The therapy was with no effect only in one patient with primary amyloidosis of kidneys.. Treatment with mycophenolate mofetil (Cell Cept) is an alternative modality for the management of immune glomerulopathies resistant to conventional and pulse pathogenetic therapeutic regimens. It can be a treatment of first choice.

Topics: Adult; Drug Therapy, Combination; Female; Glomerulonephritis; Humans; Immunosuppressive Agents; Kidney; Male; Microscopy, Fluorescence; Mycophenolic Acid; Prednisolone; Proteinuria; Treatment Outcome

The immunosuppressant mycophenolic acid (MMF) has been used successfully to manage proliferative forms of systemic lupus erythematosus (SLE) glomerulonephritis (GN) World Health Organization (WHO) Classes III and IV. Less is known about MMF treatment of membranous SLE GN (WHO Class V, SLE MN).. We report our experience with MMF therapy in 13 consecutive SLE MN patients participating in a prospective study of risk factors for SLE flare.. Baseline characteristics were: mean age 33 +/- 14 SD years, female/male ratio 11/2, Caucasians 7, African Americans 5, Oriental 1, serum creatinine 1.02 +/- 0.41, and mean 24-hour urine protein (P)/creatinine (C), ratio 5.1 +/- 4.1. Initial therapy was prednisone mean dose 31 +/- 17 mg/day, and MMF mean dose 1173 +/- 746 mg/day. Therapy also featured interventions to achieve renoprotection and proteinuria reduction. At 6 months of therapy, complete or partial remission was achieved in 10 of 13 patients. At most recent follow-up visit (mean follow-up 16 +/- 8 months), 9 of 13 patients were in complete remission, and in 11 of 13 patients, urine P/C ratio was < 0.8. During follow-up, serum creatinine either stabilized or was improved. The only serious complication during 208 patient months of follow-up was histoplasma pneumonia in 1 patient.. These promising results suggest that moderate dose MMF in combination with renoprotective/antiproteinuria therapy warrants further study in the management of SLE MN.

Topics: Adult; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Lupus Nephritis; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Proteinuria; Remission Induction; Risk Factors

Mycophenolate mofetil (MMF) is an immunosuppressive drug widely used in solid organ transplantation, and it may play an increasing role in autoimmune disease. MMF has been introduced as a novel immunosuppressive agent in systemic lupus erythematosus (SLE), often in patients intolerant of or resistant to conventional immunosuppressive regimens.. We studied 21 patients with SLE, most of whom had previously received courses of cyclophosphamide therapy and had also received courses of azathioprine or methotrexate. Indications for treatment included uncontrolled disease activity and worsening renal involvement.. MMF treatment resulted in reduced disease activity, as assessed by the SLEDAI (SLE disease activity index) (P=0.0001) and decreased proteinuria (P=0.027) while allowing a significant reduction in oral corticosteroid dose (P=0.0001). Levels of complement factors C3 and C4 and anti-double-stranded DNA antibodies were not significantly affected.. MMF appears to be a safe and effective alternative immunosuppressant for extra-renal and renal disease in SLE not responding to conventional immunosuppressive treatment.

Topics: Adult; Antibodies, Antinuclear; Azathioprine; Cyclophosphamide; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Male; Methotrexate; Middle Aged; Mycophenolic Acid; Proteinuria; Racial Groups; Statistics, Nonparametric; Time Factors; Treatment Failure

Topics: Adrenal Cortex Hormones; Creatinine; Drug Administration Schedule; Europe; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Patient Selection; Prednisone; Proteinuria; Tacrolimus

Treatment of primary glomerular diseases may be unsuccessful or have potential toxicities. Therefore, we evaluated the use of mycophenolate mofetil (MMF) for empirical treatment of primary glomerulopathies.. Forty-six patients with biopsy-proven primary glomerulopathies received MMF for > or =3 months as adjunctive or primary treatment. Median (range) 24-hour urine protein to creatinine ratio (Up/c) and serum creatinine at the start and end of MMF therapy were compared using the Wilcoxon signed-ranks test.. Overall, the median Up/c decreased from 4.7 (range <0.1, 20.3) to 1.1 (<0.1, 14.3; P < 0.001) at the end of MMF treatment with no significant change in median serum creatinine 1.3 (0.6 to 6.1) to 1.2 (0.5 to 6.5) mg/dL. Median serum albumin increased from 3.4 (1.4, 4.6) to 4.1 (1.7, 48) g/dL (P < 0.001) and the median serum cholesterol decreased from 270 (148, 795) to 220 (140, 309) mg/dL (P < 0.001) post-treatment. For those with minimal change disease, a complete steroid withdrawal was accomplished in 5/6 steroid dependent patients. Focal segmental glomerulosclerosis (FSGS) patients had a median Up/c that decreased from 2.7 (0.1, 20.3) to 0.8 (<0.1, 8.2; P = 0.001) in 18 patients. In membranous nephropathy (MN) patients, the median Up/c decreased from 7.3 (0.1, 18.5) to 1.5 (<0.1, 14.3) (P = 0.001) in 17 patients. No significant change in median serum creatinine was detected in FSGS or MN patient groups during treatment.. Empirical MMF therapy in the majority of patients with primary glomerulopathies was well tolerated and achieved the goals of steroid withdrawal, improvement of nephrotic syndrome, and stabilization of renal function.

Topics: Adolescent; Adult; Aged; Creatinine; Female; Glomerulonephritis, Membranous; Glomerulosclerosis, Focal Segmental; Humans; Kidney Diseases; Kidney Glomerulus; Male; Middle Aged; Mycophenolic Acid; Nephrosis, Lipoid; Proteinuria; Steroids

Topics: Azathioprine; Biopsy; Blood Pressure; Cholesterol; Creatinine; Cyclosporine; Drug Therapy, Combination; Female; Humans; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Male; Mycophenolic Acid; Postoperative Complications; Prednisone; Proteinuria; Tacrolimus; Triglycerides

Inducing and maintaining remission in patients with lupus nephritis may be difficult. Current treatments have significant toxicity. Mycophenolate mofetil (MMF) limits damage in murine models of lupus nephritis. We have assessed the efficacy and tolerability of MMF in the treatment of patients with long-standing or resistant lupus nephritis. We have treated 13 patients with biopsy proven lupus nephritis (two membranous nephropathy, four membranous nephropathy with superimposed proliferative changes, seven with proliferative glomerulonephritis). All patients had relapsed on conventional treatment or there were pressing indications to minimise steroid dosage or avoid alkylating agents. Nine out of 13 were treated with MMF and prednisolone, 3/10 with MMF alone and 1/10 with MMF, prednisolone and cyclosporine. Thirteen patients were treated with MMF for up to 37 months (median 25 months). Three patients were withdrawn from MMF during the first 8 months of treatment. The remainder tolerated MMF (median dose 1 g/day). Serological improvements were observed in 9/13 and steroid dosage was reduced in 8/10 patients. Infections occurred in 3/13. One patient relapsed. MMF significantly reduced the rate of decline of renal function. MMF should be considered in the treatment of long-standing or resistant lupus nephritis. Controlled clinical trials are required to confirm these findings.

Topics: Adrenal Cortex Hormones; Adult; Blood Pressure; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Infections; Kidney Failure, Chronic; Lupus Nephritis; Middle Aged; Mycophenolic Acid; Patient Dropouts; Pilot Projects; Proteinuria; Severity of Illness Index; Treatment Outcome

Membranous nephropathy (MN) is a common cause of nephrotic syndrome. Optimal therapy for this disease is still debated. We report our experience using mycophenolate mofetil (MMF), an immunosuppressive agent widely used in transplant recipients, to treat 16 nephrotic patients with MN. All patients had biopsy-documented MN; secondary forms were ruled out. Fifteen patients had steroid-resistant disease; cytotoxic agents had failed in 6 patients and cyclosporine therapy had failed in 5 patients. Patients were treated with MMF (dose range, 500 to 2,000 mg) for a mean of 8 months. Six patients experienced a halving of proteinuria, which occurred after a mean duration of 6 months of therapy. Partial remissions occurred in 2 patients. There were no significant changes in mean values for serum creatinine, serum albumin, or proteinuria. Mean cholesterol levels were significantly less. Side effects of MMF were infrequent and generally mild. In summary, MMF appears to reduce proteinuria in some patients with idiopathic MN previously resistant to steroids, cytotoxic agents, or cyclosporine. Further trials with this agent are warranted.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Inflammatory Agents, Non-Steroidal; Cholesterol; Creatinine; Female; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Pilot Projects; Proteinuria

Topics: Adult; Aged; Creatinine; Cyclosporine; Female; Glomerular Filtration Rate; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Proteinuria

C3-glomerulopathy (C3G) is a rare pediatric kidney disease characterised by dysregulation of the alternative complement pathway, with glomerular deposition of C3. C3G may often present as a steroid-resistant nephrotic syndrome (SRNS), and there is no established effective therapy: the usual treatment involves corticosteroids and immunosuppressive drugs. Pioglitazone, a PPAR-γ agonist with a protective action on podocytes, was reported in a few cases as helpful in reducing proteinuria when combined with steroids.. We report the case of a 13-year-old girl with silent past medical history who presented with SRNS. A kidney biopsy showed findings indicative of C3G. A low sodium diet and angiotensin-converting enzyme inhibitor were started; immunosuppressive treatment with mycophenolate mofetil (MMF) was administered due to the cortico-resistance. Because of poor response to the immunosuppressant, a trial with eculizumab was attempted without significant response and persistence of proteinuria in the nephrotic range. A further therapeutic trial was performed with tacrolimus with no disease remission. Due to a severe deterioration in her condition, the girl was hospitalized and treated with high-dose steroid bolus. A daily dose of oral prednisone and MMF were re-started without benefit with persistent levels of nephrotic range proteinuria. The administration of pioglitazone consistently lowered proteinuria levels for the first time since the onset of the disease, with a maintenance of the effect and normalization (< 0.15 g/24 h) at the 10-month follow-up.. In this patient affected by C3G, pioglitazone proved effective in reducing proteinuria levels.

Topics: Adolescent; Female; Humans; Immunosuppressive Agents; Mycophenolic Acid; Nephrotic Syndrome; Peroxisome Proliferator-Activated Receptors; Pioglitazone; Prednisone; Proteinuria; Treatment Outcome

The use of human serum albumin (HSA) is described in dogs receiving critical care. However, despite the high degree of homology, anaphylactic and delayed hypersensitivity reactions are reported. Delayed type III hypersensitivity reactions can lead to glomerulonephritis and acute kidney injury (AKI). Undiluted 20% HSA was administered to a 4.8 yr old intact male Labrador Retriever with severe hypoalbuminemia, following surgical management of septic peritonitis of gastrointestinal origin. Nineteen days after HSA administration, the dog developed peracute high magnitude renal proteinuria and AKI. Rapid immunosuppression, using a combination of prednisolone and mycophenolate mofetil, resulted in full resolution of AKI, hypoalbuminemia, and proteinuria. Addition of mycophenolate mofetil may have resulted in the first documented case of full renal recovery from hypersensitivity-induced AKI caused by HSA administration.

Topics: Acute Kidney Injury; Animals; Dog Diseases; Dogs; Humans; Hypoalbuminemia; Immunosuppressive Agents; Male; Mycophenolic Acid; Prednisolone; Proteinuria; Serum Albumin, Human

C3 glomerulonephritis (C3GN) can be a devastating disease with poor response to immunosuppressive therapy. Complement inhibition with eculizumab has had equivocal results in patients with C3GN.. We report a case of a 6-year-old boy with C3GN presenting with nephrotic syndrome, severe hypertension and impaired kidney function. He did not respond to initial treatment with prednisone and mycophenolate (mofetil and sodium), and subsequent treatment with standard dosing of eculizumab. Pharmacokinetic studies identified a lack of eculizumab exposure and subsequent intensification of treatment with weekly dosing of eculizumab led to significant clinical improvement: his kidney function normalized, hypertension (weaned off 3 antihypertensive drugs), edema and proteinuria improved. Additionally, exposure to mycophenolic acid (MPA), active metabolite of mycophenolate, determined by area under the concentration-time curve of MPA was low throughout, despite significant dosing escalation.. This case report demonstrates that individualized therapy guided by therapeutic drug monitoring might be needed in patients with nephrotic range proteinuria treated with eculizumab and mycophenolate (mofetil and sodium), an important finding that needs to be considered for further treatment trials.

Topics: Child; Drug Monitoring; Glomerulonephritis; Humans; Hypertension; Immunosuppressive Agents; Male; Mycophenolic Acid; Proteinuria

There is no standard recommendation for IgA nephropathy treatment in children.. This is a retrospective study. From 2012 to 2020, newly diagnosed primary IgAN followed up for at least 1 year were enrolled. The correlation of MESTC scores and clinical index including proteinuria, gross hematuria and renal dysfunction was analyzed. Treatment and clinical response of 6 month, 1year and 3 year at follow up were also analyzed. Complete renal remission was calculated with Kaplan-Meier analysis.. The median follow up was 36 months, from 12 months to 87months in 40 IgAN children. Angiotensin-converting enzyme inhibitor (ACEI) was applied to all patients. 30% received ACEI alone; 15% received glucocorticoids; 37.5% received glucocorticoids plus cyclophosphamide, 17.5% received glucocorticoids plus mycophenolate mofetil. Individuals with diffuse mesangial hypercellularity (M1) were more likely to have nephrotic range proteinuria compared to patients with M0 (80% vs. 20%, P < 0.01). Complete renal remission at 6-month, 1-year and 3-year follow up is 50.25%, 70% and 87.5% respectively. Five-year complete renal remission calculated by Kaplan-Meier analysis is 58.4%. Although without significant difference, there is trend of better survival with complete renal remission in group of nephrotic range proteinuria onset. There is no severe adverse effect.. This study supports the use of glucocorticoids plus immunosuppressive in addition to ACEI in IgA nephrology pediatric patients with proteinuria. We suggest proactive immunosuppressive treatment in IgA nephropathy in children. This is from a single center in China as may not same results in other population.

Topics: Angiotensin-Converting Enzyme Inhibitors; Biopsy; CD4-Positive T-Lymphocytes; Child; China; Cyclophosphamide; East Asian People; Female; Follow-Up Studies; Glomerulonephritis, IGA; Glucocorticoids; Hematuria; Humans; Immunosuppressive Agents; Intraocular Pressure; Kaplan-Meier Estimate; Kidney Diseases; Male; Mycophenolic Acid; Proteinuria; Retrospective Studies; Survival Analysis; Time Factors; Treatment Outcome

Children with severe Henoch-Schönlein purpura nephritis (HSPN) may progress to end-stage renal disease without appropriate treatment.. This study aimed to investigate the efficacy and safety of tacrolimus combined with glucocorticoids in the treatment of pediatric HSPN.. A total of 87 HSPN patients with urinary protein ≥ 0.75 g/24 h received standard of care, including angiotensin II receptor blockers/angiotensin-converting enzyme inhibitors and glucocorticoids. Patients were divided into three groups and additionally received tacrolimus (n = 30), cyclophosphamide (n = 31), or mycophenolate mofetil (MMF) (n = 26). We monitored outcome measures, including proteinuria, hematuria, and renal function and analyzed the efficacy and side effects in each group.. At 2-month follow-up, the overall efficacy was 93.3%, 83.9%, and 61.5% for tacrolimus, cyclophosphamide, and MMF, respectively (P < 0.05). Urinary protein significantly decreased for all groups. Urinary red blood cell counts significantly decreased for patients treated with tacrolimus (P < 0.001) and cyclophosphamide (P < 0.05), whereas no significant decrease was seen for those receiving MMF (P = 0.09). Although urine β2-microglobulin significantly decreased following 2 months of treatment with all medications, efficacy was greater with tacrolimus than with cyclophosphamide and MMF (P < 0.001). Major adverse events were respiratory and urinary infections, with MMF having the highest infection rate. The cyclophosphamide group also experienced additional adverse events, including arrhythmia, hemorrhagic cystitis, leukocytosis, thrombocytopenia, and hyperglycemia.. These results indicate that tacrolimus is more effective at reducing proteinuria and hematuria and improving renal function, with relatively milder side effects, in the treatment of pediatric HSPN.. ChiCTR2200055323, retrospectively registered on January 7, 2022.

Topics: Child; Cyclophosphamide; Glucocorticoids; Hematuria; Humans; IgA Vasculitis; Immunosuppressive Agents; Mycophenolic Acid; Nephritis; Proteinuria; Tacrolimus

Augmentation of intrarenal angiotensinogen (AGT) leads to further formation of intrarenal angiotensin II (Ang II) and the development of hypertensive kidney injury. Recent studies demonstrated that macrophages and the enhanced production of pro-inflammatory cytokines can be crucial mediators of renal AGT augmentation in hypertension. Accordingly, this study investigated the effects of immunosuppression by mycophenolate mofetil (MMF) on intrarenal AGT augmentation. Ang II (80 ng/min) was infused with or without daily administration of MMF (50 mg/kg) to Sprague-Dawley rats for 2 weeks. Mean arterial pressure (MAP) in Ang II infused rats was slightly higher (169.7 ± 6.1 mmHg) than the Ang II + MMF group (154.7 ± 2.0 mmHg), but was not statistically different from the Ang II + MMF group. MMF treatment suppressed Ang II-induced renal macrophages and IL-6 elevation. Augmentation of urinary AGT by Ang II infusion was attenuated by MMF treatment (control: 89.3 ± 25.2, Ang II: 1194 ± 305.1, and Ang II + MMF: 389 ± 192.0 ng/day). The augmentation of urinary AGT by Ang II infusion was observed before the onset of proteinuria. Elevated intrarenal AGT mRNA and protein levels in Ang II infused rats were also normalized by the MMF treatment (AGT mRNA, Ang II: 2.5 ± 0.2 and Ang II + MMF: 1.5 ± 0.1, ratio to control). Ang II-induced proteinuria, mesangial expansion and renal tubulointerstitial fibrosis were attenuated by MMF. Furthermore, MMF treatment attenuated the augmentation of intrarenal NLRP3 mRNA, a component of inflammasome. These results indicate that stimulated cytokine production in macrophages contributes to intrarenal AGT augmentation in Ang II-dependent hypertension, which leads to the development of kidney injury.

Topics: Angiotensin II; Angiotensinogen; Animals; Blood Pressure; Hypertension; Immunosuppression Therapy; Kidney; Kidney Diseases; Mycophenolic Acid; Proteinuria; Rats; Rats, Sprague-Dawley; RNA, Messenger

A 3-year-old entire female Springer Spaniel, with a previous diagnosis of meningoencephalitis of unknown origin diagnosed 2 years before presentation and treated with long term administration of prednisolone, developed proteinuria. Laboratory findings revealed hypoalbuminemia, hypercholesterolemia, and proteinuria. Further investigations excluded underlying causes. Renal biopsies were performed. The glomeruli and the tubulointerstitial compartment did not show any anomalies on light microscopy and immunofluorescence staining did not reveal abnormalities. Transmission electron microscopy revealed moderate podocyte injury consisting of foot process effacement and microvillus transformation of the cytoplasm. The dog was diagnosed with primary minimal change disease of the podocytes and treated with telmisartan and mycophenolate mofetil. Abnormalities of serum albumin, cholesterol, and proteinuria resolved within 4 weeks. Minimal change disease has been reported in dogs, but this is a case report of proteinuria secondary to minimal change disease successfully treated with mycophenolate mofetil and telmisartan.

Topics: Animals; Dog Diseases; Dogs; Female; Kidney Glomerulus; Mycophenolic Acid; Nephrosis, Lipoid; Proteinuria; Telmisartan

Topics: Humans; Immunosuppressive Agents; Lupus Nephritis; Mycophenolic Acid; Proteinuria; Treatment Outcome

Lupus nephritis requires antinuclear antibodies as classification criteria. There is a group of patients with nephrotic syndrome and conclusive histopathological findings for lupus nephritis, without classification criteria for systemic lupus erythematosus (SLE) or extrarenal manifestations. These groups of patients have been described as "lupus-like" nephritis or "renal-limited lupus nephritis".. Renal biopsy with histopathological evaluation with "full-house" immune-reactants in patients with negative antinuclear antibodies.. We report four cases with nephrotic syndrome and one with hematuria-proteinuria syndrome: two with impaired glomerular filtration rate and three with preserved renal function; urinary sediment with hematuria without dysmorphia and without extrarenal manifestations for autoimmune disease, negative antinuclear antibodies (ANA) and anti-double stranded DNA (anti-dsDNA); normal C3 and C4 complement levels. Renal biopsy in all cases was consistent for lupus nephritis class V. All patients received treatment as lupus nephritis protocol; only one case received induction with cyclophosphamide and methylprednisolone boluses, the rest received mycophenolic acid and prednisone as induction and maintenance. Two of the cases induced with mycophenolic acid relapsed, requiring cyclophosphamide for 6 months, achieving complete remission. All patients received renin-angiotensin-aldosterone system blockade and hydroxychloroquine. At follow-up, 4 cases still have negative antibodies and are without extrarenal manifestations for SLE classification criteria. The other case, during pregnancy several years after initial diagnosis, had preeclampsia with nephrotic proteinuria and a new determination of positive ANA and anti-dsDNA antibodies, complement levels below normal limits.. The follow-up of patients with membranous glomerulopathy must be close; lupus like nephritis may be the first manifestation of the disease.

Topics: Antibodies, Antinuclear; Complement System Proteins; Cyclophosphamide; Female; Glomerulonephritis, Membranous; Hematuria; Hospitals; Humans; Lupus Erythematosus, Systemic; Lupus Nephritis; Mexico; Mycophenolic Acid; Pregnancy; Proteinuria

Nephritis occurs frequently in systemic lupus erythematosus (SLE) and may worsen disease morbidity and mortality. Knowing all characteristics of this manifestation helps to a prompt recognition and treatment.. To compare the differences in clinical data, serological profile and treatment response of nephritis of early and late onset.. Retrospective study of 71 SLE patients with biopsy proven nephritis divided in early nephritis group (diagnosis of nephritis in the first 5 years of the disease) and late nephritis (diagnosis of nephritis after 5 years). Epidemiological, serological, clinical and treatment data were collected from charts and compared.. In this sample, 70. 4% had early onset nephritis and 29.6% had late onset. No differences were noted in epidemiological, clinical, serological profile, SLICC and SLEDAI, except that late onset nephritis patients were older at nephritis diagnosis (p = 0.01). Regarding renal biopsy classification, C3 and C4 levels, serum creatinine, 24 h proteinuria and response rate to treatment the two groups were similar (p = NS). Patients with early onset had lower levels of hemoglobin at nephritis onset than those of late onset (p = 0.02).. Most of SLE patients had nephritis in the first 5 years of disease. No major differences were noted when disease profile or treatment outcome of early and late onset nephritis were compared.

Topics: Adult; Azathioprine; Biopsy; Complement C3; Complement C4; Creatinine; Cyclophosphamide; Delayed Diagnosis; Early Diagnosis; Female; Hemoglobin A; Humans; Immunosuppressive Agents; Induction Chemotherapy; Lupus Erythematosus, Systemic; Lupus Nephritis; Maintenance Chemotherapy; Male; Mycophenolic Acid; Proteinuria; Retrospective Studies; Time Factors; Young Adult

To update the 2012 EULAR/ERA-EDTA recommendations for the management of lupus nephritis (LN).. Following the EULAR standardised operating procedures, a systematic literature review was performed. Members of a multidisciplinary Task Force voted independently on their level of agreeement with the formed statements.. The changes include recommendations for treatment targets, use of glucocorticoids and calcineurin inhibitors (CNIs) and management of end-stage kidney disease (ESKD). The target of therapy is complete response (proteinuria <0.5-0.7 g/24 hours with (near-)normal glomerular filtration rate) by 12 months, but this can be extended in patients with baseline nephrotic-range proteinuria. Hydroxychloroquine is recommended with regular ophthalmological monitoring. In active proliferative LN, initial (induction) treatment with mycophenolate mofetil (MMF 2-3 g/day or mycophenolic acid (MPA) at equivalent dose) or low-dose intravenous cyclophosphamide (CY; 500 mg × 6 biweekly doses), both combined with glucocorticoids (pulses of intravenous methylprednisolone, then oral prednisone 0.3-0.5 mg/kg/day) is recommended. MMF/CNI (especially tacrolimus) combination and high-dose CY are alternatives, for patients with nephrotic-range proteinuria and adverse prognostic factors. Subsequent long-term maintenance treatment with MMF or azathioprine should follow, with no or low-dose (<7.5 mg/day) glucocorticoids. The choice of agent depends on the initial regimen and plans for pregnancy. In non-responding disease, switch of induction regimens or rituximab are recommended. In pure membranous LN with nephrotic-range proteinuria or proteinuria >1 g/24 hours despite renin-angiotensin-aldosterone blockade, MMF in combination with glucocorticoids is preferred. Assessment for kidney and extra-renal disease activity, and management of comorbidities is lifelong with repeat kidney biopsy in cases of incomplete response or nephritic flares. In ESKD, transplantation is the preferred kidney replacement option with immunosuppression guided by transplant protocols and/or extra-renal manifestations. Treatment of LN in children follows the same principles as adult disease.. We have updated the EULAR recommendations for the management of LN to facilitate homogenization of patient care.

Topics: Antirheumatic Agents; Azathioprine; Calcineurin Inhibitors; Drug Therapy, Combination; Europe; Glomerular Filtration Rate; Glucocorticoids; Humans; Hydroxychloroquine; Immunosuppressive Agents; Kidney Failure, Chronic; Lupus Nephritis; Mycophenolic Acid; Proteinuria; Societies, Medical

In patients with LN, clinical and histological responses to treatment have been shown to be discordant. We investigated whether per-protocol repeat kidney biopsies are predictive of LN relapses and long-term renal function impairment.. Forty-two patients with incident biopsy-proven active proliferative (class III/IV±V) LN from the database of the UCLouvain were included in this retrospective study. Per-protocol repeat biopsies were performed after a median [interquartile range (IQR)] time of 24.3 (21.3-26.2) months. The National Institutes of Health activity index (AI) and chronicity index (CI) scores were assessed in all biopsies.. Despite a moderate correlation between urinary protein/creatinine ratios (UPCR) and AI scores at repeat biopsy (r = 0.48; P = 0.001), 10 patients (23.8%) with UPCR < 1.0 g/g still had a high degree of histological activity (AI > 3). High AI scores (continuous) in repeat biopsies were associated with an increased probability and/or shorter time to renal relapse (n = 11) following the repeat biopsy [hazard ratio (HR) = 1.2, 95% CI: 1.1, 1.3; P = 0.007], independently of proteinuria levels. High CI scores (continuous) in repeat biopsies were associated with a sustained increase in serum creatinine levels corresponding to ≥120% of the baseline value (HR = 1.8, 95% CI: 1.1, 2.9; P = 0.016) through a median (IQR) follow-up time of 131.5 (73.8-178.2) months, being also the case for acute tubulointerstitial inflammation and interstitial fibrosis/tubular atrophy in repeat but not baseline biopsies.. Our results highlight the usefulness of per-protocol repeat biopsies, herein performed after a median time of 24 months from baseline, as an integral part of the treatment evaluation, also in patients showing adequate clinical response.

Topics: Adult; Biopsy; Creatinine; Cyclophosphamide; Disease Progression; Female; Glucocorticoids; Humans; Immunologic Factors; Immunosuppressive Agents; Kidney; Kidney Tubules; Lupus Nephritis; Male; Methylprednisolone; Mycophenolic Acid; Prognosis; Proportional Hazards Models; Proteinuria; Pulse Therapy, Drug; Recurrence; Retrospective Studies; Rituximab; Young Adult

A 34-year-old female patient presented to our hospital with lower extremity edema and proteinuria during pregnancy. Renal biopsy was performed and the patient was diagnosed with nephrotic syndrome due to lupus-like membranous nephropathy. This diagnosis was reached upon as laboratory findings upon admission, wherein both anti-nuclear and anti-double-stranded DNA antibodies revealed negative, did not fulfill the criteria for systemic lupus erythematosus (SLE) proposed by the American College of Rheumatology (ACR) and the patient did not reveal any typical physical manifestations of SLE. Methylprednisolone pulse therapy was started followed by oral administration of prednisolone. Urinary protein excretion diminished after 1 year of treatment. Eleven years later, the same patient was admitted to our hospital again with relapse of nephrotic syndrome. Laboratory findings upon second admission, wherein both anti-nuclear and anti-double-stranded DNA antibodies revealed positive, fulfilled the ACR criteria. Renal biopsy was performed again, resulting in a diagnosis of lupus nephritis. Steroid therapy combined with administration of mycophenolate mofetil led to an incomplete remission. Immunofluorescence studies confirmed the presence of IgG, IgM, C3, and C1q in renal biopsy specimens both at first and second admissions. Furthermore, immunofluorescence studies confirmed the presence of IgG1-4 in the first biopsy and tubuloreticular inclusions (TRIs) were revealed using electron microscopy. The present case represents the possibility that characteristic pathological findings of lupus nephritis, including TRIs, can reveal themselves before a diagnosis of SLE.

Topics: Adult; Antibodies, Antinuclear; Drug Therapy, Combination; Enzyme Inhibitors; Female; Glomerulonephritis, Membranous; Glucocorticoids; Hospitalization; Humans; Immunoglobulin G; Kidney; Lupus Erythematosus, Systemic; Lupus Nephritis; Methylprednisolone; Mycophenolic Acid; Nephrotic Syndrome; Proteinuria; Recurrence; Remission Induction

Favourable long-term prognosis in proliferative lupus nephritis (LN) is associated with the achievement of complete renal response (CR), which is defined as a urine protein/creatinine ratio (UPCR) of < 0.5. However, it is unclear whether a more stringent cut-off for proteinuria (normal value of proteinuria; UPCR < 0.15) is better than CR. We aimed to evaluate the effect of stringent CR, defined as a UPCR of <0.15, on long-term renal outcomes in proliferative LN.. We included 87 patients with class III or IV LN who achieved CR at one year after induction therapy. Clinical and laboratory data were compared between the stringent and non-stringent CR groups. Logistic regression analysis was performed to identify factors associated with achievement of stringent CR. Cox analysis was performed to analyse the risk factors for renal flare and development of chronic kidney disease (CKD).. Achievement of stringent CR predicted lower risk of renal flare and development of CKD in proliferative LN. These findings suggest that stringent CR is a valuable treatment target in proliferative LN.

Topics: Adult; Female; Humans; Immunosuppressive Agents; Lupus Nephritis; Male; Middle Aged; Mycophenolic Acid; Prognosis; Proteinuria; Remission Induction; Retrospective Studies; Risk Factors; Treatment Outcome; Young Adult

Immunoglobulin (Ig)G4-related disease (IgG4-RD) is an unusual complication of systemic lupus erythematosus (SLE). We report a case in which belimumab proved efficacious for not only SLE, but also IgG4-RD. A 58-year-old Japanese woman had suffered from photodermatosis and erythema on the limbs for 20 years. She presented in slight fever and fatigue since 2016. Laboratory data showed hypergammaglobulinemia, proteinuria and positive results for anti-nuclear antibody and anti-double-stranded DNA antibody. Furthermore, elevated levels of serum IgG4 were detected. Contrast-enhanced computed tomography disclosed multiple areas of poor enhancement in the kidneys. The patient was diagnosed with lupus nephritis and IgG4-RD from renal biopsy. Treatment was started with prednisolone at 40 mg/day and mycophenolate mofetil. Proteinuria and serological findings improved initially, but tapering the dose of glucocorticoid proved difficult. After treatment was started with belimumab, clinical symptoms and proteinuria resolved completely. The dose of glucocorticoid was successfully tapered and serum concentration of IgG4 fell further. This appears to represent the first report of a case in which both SLE and IgG4-RD were effectively treated using belimumab.

Topics: Antibodies, Antinuclear; Antibodies, Monoclonal, Humanized; Female; Fever; Humans; Immunoglobulin G4-Related Disease; Immunosuppressive Agents; Kidney; Lupus Nephritis; Middle Aged; Mycophenolic Acid; Proteinuria; Tomography, X-Ray Computed

Since there are only a few reports on pediatric systemic lupus erythematosus (pSLE) in Chinese populations, therefore we retrospectively report the clinical and immunological features as well as renal outcome in Chinese pSLE.. Patients diagnosed with pSLE at Shanghai Children's Medical Center between 2001 and 2016 were evaluated and clinical data were retrospectively collected.. A total of 102 pSLE patients were analyzed. Renal disorder including proteinuria (81.37%) and hematuria (65.69%) were most commonly identified. Class IV was the most common finding on renal biopsy. In lupus nephritis (LN), 67.21%, 78.0%, 86.0% and 94.55% achieved complete remission within 6, 12, 18 and 24 months, respectively. Furthermore, 16.67% of LN patients suffered at least one renal flare. Antinuclear antibodies were detected in nearly all patients (97.62%), followed by anti-double-stranded DNA (anti-dsDNA) antibodies (70.0%) and anti-Sjögren's syndrome A (anti-SSA) antibodies (60.64%). Oral corticosteroid (93.14%) and mycophenolate mofetil (64.71%) was used in the majority of patients. Infection (32.35%) was the main side effect caused by the medications.. Our population-based pSLE cohort indicated that compared to other international cohorts, there was a higher prevalence of LN in Chinese pSLE. Proteinuria was the most frequent manifestation both at disease onset and during the entire clinical course. Class IV LN was the dominant renal pathological type. Nevertheless, there was a favorable renal remission rate and relatively low incidence of renal flare in our cohort. Apart from antinuclear antibodies and anti-dsDNA antibodies, anti-SSA antibodies were most frequently detected. Infection was the leading complication caused by the medications.

Topics: Adolescent; Adrenal Cortex Hormones; Age of Onset; Antibodies, Antinuclear; Biomarkers; Child; China; Female; Hematuria; Humans; Immunocompromised Host; Incidence; Lupus Erythematosus, Systemic; Lupus Nephritis; Male; Mycophenolic Acid; Opportunistic Infections; Prevalence; Proteinuria; Remission Induction; Retrospective Studies; Risk Factors; Time Factors; Treatment Outcome

The Henoch-Schönlein Purpura (HSP) orIgA vasculitis is the most common vasculitis of childhood and may occur with renal involvement, with hematuria and / or proteinuria, and may cause severe and non-reversible sequelae.. To establish the profile of patients with renal involvement due to IgA vasculitisand to describe our experience with the use of azathioprine to treat patients with nephritis.. Clinical data were retrospectively collected from medical records of patients with IgA vasculitiswho attended the pediatric rheumatology unit between 1995 and 2017. Patients were separated into two groups based on whether or notthey weretreated with non-glucocorticoid immunosuppressants.. From the178 patients with IgA vasculitis,nephritis was found in67 patients (37.6%), 13 of whom receivedtreatment with non-glucocorticoid immunosuppressants. Ten patients responded well to azathioprine and 1 patient to cyclosporine. Forty patients received oral glucocorticoids, whilst 16received intravenous glucocorticoids.. Azathioprine may be beneficial in the treatment of IgA vasculitis with renal involvement.

Topics: Adolescent; Antirheumatic Agents; Azathioprine; Child; Child, Preschool; Cyclophosphamide; Female; Hematuria; Humans; IgA Vasculitis; Immunosuppressive Agents; Male; Mycophenolic Acid; Nephritis; Proteinuria; Retrospective Studies; Treatment Outcome

To study the response of lupus nephritis (LN) patients with persistent proteinuria (≥ 1 g/day after ≥ 6 months corticosteroid and single immunosuppressant treatment, or ≥ 3 g/day after ≥ 3 months of corticosteroid and single immunosuppressant treatment) to corticosteroid combined with two immunosuppressants, and to evaluate associated factors of response within 1 year.. A retrospective study of proteinuria and renal function observed in LN patients with persistent proteinuria after adding a second immunosuppressant at 3, 6, 9 and 12 months.. Twenty-one LN patients (100.0% female) with persistent proteinuria were treated with corticosteroid and two immunosuppressants (mycophenolate mofetil [MMF] plus cyclosporine A [CSA]). Their mean age and duration from first immunosuppressant to initiating a combination therapy were 33.2 ± 10.2 years and 17.5 ± 15.7 months, respectively. Twelve (57.1%) patients had proteinuria levels ≥ 3 g/day. The renal pathology from 18 patients were Classes III or IV in 11 (61.1%). Fifteen patients (71.4%) responded to treatment (complete remission [CR], proteinuria ≤ 0.5 g/day, in seven patients and partial remission [PR], proteinuria reduced > 50%, in eight patients). Changing from a single immunosuppressant to combined immunosuppressants was associated with CR within 1 year (hazards ratio = 0.88; 95% CI = 0.78-0.99). Adverse events consisted of one patient with severe infection, two herpes zoster and one with transient increased serum creatinine level.. Approximately 70% of LN patients with persistent proteinuria responded to MMF plus CSA. However, infection should be a concern with these patients.

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Cyclosporine; Drug Therapy, Combination; Female; Humans; Immunocompromised Host; Immunosuppressive Agents; Lupus Nephritis; Male; Mycophenolic Acid; Opportunistic Infections; Proteinuria; Remission Induction; Retrospective Studies; Time Factors; Treatment Outcome; Young Adult

Henoch-Schönlein purpura (HSP) is the most common vasculitis in childhood and traditionally considered as a self-limiting disease. However, renal involvement can unfavorably determine long-term prognosis. The reported regimens to treat HSP nephritis (HSPN) are diverse, indicating that the most effective treatment remains controversial.. This retrospective, single-center study involved 18 patients presenting with HSPN and nephrotic-range proteinuria. We aimed to investigate the efficacy and safety of mycophenolate mofetil (MMF) and identify a cut-off level for estimated mycophenolic acid area under the curve (eMPA-AUC

Topics: Adolescent; Child; Child, Preschool; Drug Monitoring; Enzyme Inhibitors; Female; Germany; Glucocorticoids; Humans; IgA Vasculitis; Kidney; Male; Mycophenolic Acid; Nephritis; Proteinuria; Retrospective Studies; ROC Curve; Treatment Outcome

The widely used International Study of Kidney Disease in Children (ISKDC) classification for Henoch-Schönlein purpura nephritis (HSPN) does not completely correlate with the clinical presentation and long-term prognosis of this disease. Primary IgA nephropathy (IgAN) and HSPN share common features; thus, the Oxford classification of IgAN might be useful in predicting the long-term outcomes of HSPN. However, its value has not been confirmed in children with HSPN.. We selected children with HSPN diagnosed between 2003 and 2015, and reclassified their renal biopsies according to the Oxford classification scoring system. The primary outcome was impaired renal function, and remission of proteinuria and clinical remission were secondary outcomes.. We included 104 patients (58 males, 46 females) with a median age of 10 (4-17) years. Mesangial hypercellularity (M1) was strongly associated with proteinuria, and tubular atrophy/interstitial fibrosis (T1&2) and C2 (with crescents in > 25% of glomeruli) were associated with reduced estimated glomerular filtration rate (eGFR) at the time of biopsy. Patients with M1, endocapillary proliferation (E1), segmental glomerulosclerosis (S1), and crescents (C1&2) were more likely to have been treated with high-dose methylprednisolone. At univariate time-dependent analyses, S1 was strongly associated with the primary outcome (p = 0.025), whereas T1&2 was significantly negatively associated with proteinuria remission (p = 0.035) and clinical remission (p = 0.038).. Our findings suggest that the Oxford classification is valid for children with HSPN. S and T lesions, which are ignored in the ISKDC classification, can be used to assess renal outcomes of HSPN, and such assessments are not affected by currently available treatments. The value of M, E and C lesions in predicting response to therapy and renal outcome warrants further study.

Topics: Adolescent; Anti-Inflammatory Agents; Antibiotics, Antineoplastic; Atrophy; Biopsy; Child; Child, Preschool; Cyclophosphamide; Female; Fibrosis; Glomerular Filtration Rate; Glomerular Mesangium; Glomerulonephritis, IGA; Humans; IgA Vasculitis; Immunosuppressive Agents; Kidney Tubules; Leflunomide; Male; Methylprednisolone; Mycophenolic Acid; Proteinuria; Risk Factors

C3 glomerulopathy is a form of complement-mediated GN. Immunosuppressive therapy may be beneficial in the treatment of C3 glomerulopathy. Mycophenolate mofetil is an attractive treatment option given its role in the treatment of other complement-mediated diseases and the results of the Spanish Group for the Study of Glomerular Diseases C3 Study. Here, we study the outcomes of patients with C3 glomerulopathy treated with steroids and mycophenolate mofetil.. We conducted a retrospective chart review of patients in the C3 glomerulopathy registry at Columbia University and identified patients treated with mycophenolate mofetil for at least 3 months and follow-up for at least 1 year. We studied clinical, histologic, and genetic data for the whole group and compared data for those who achieved complete or partial remission (responders) with those who did not achieve remission (nonresponders). We compared remission with mycophenolate mofetil with remission with other immunosuppressive regimens.. We identified 30 patients who met inclusion criteria. Median age was 25 years old (interquartile range, 18-36), median creatinine was 1.07 mg/dl (interquartile range, 0.79-1.69), and median proteinuria was 3200 mg/g creatinine (interquartile range, 1720-6759). The median follow-up time was 32 months (interquartile range, 21-68). Twenty (67%) patients were classified as responders. There were no significant differences in baseline characteristics between responders and nonresponders, although initial proteinuria was lower (median 2468 mg/g creatinine) in responders compared with nonresponders (median 5000 mg/g creatinine) and soluble membrane attack complex levels were higher in responders compared with nonresponders. For those tapered off mycophenolate mofetil, relapse rate was 50%. Genome-wide analysis on complement genes was done, and in 12 patients, we found 18 variants predicted to be damaging. None of these variants were previously reported to be pathogenic. Mycophenolate mofetil with steroids outperformed other immunosuppressive regimens.. Among patients who tolerated mycophenolate mofetil, combination therapy with steroids induced remission in 67% of this cohort. Heavier proteinuria at the start of therapy and lower soluble membrane attack complex levels were associated with treatment resistance.

Topics: Adolescent; Adult; Anti-Inflammatory Agents; Complement C3; Creatinine; Drug Therapy, Combination; Exome Sequencing; Female; Glomerulonephritis, Membranoproliferative; Humans; Immunosuppressive Agents; Male; Mycophenolic Acid; Prednisone; Proteinuria; Retrospective Studies; Treatment Outcome; Young Adult

Hypocomplementemic urticarial vasculitis syndrome (HUVS) is a rare autoimmune disease characterized by multiple organ system involvement, including renal disease, with low complement levels. We report the case of a 31-year-old woman who presented with nonspecific symptoms including fatigue, diarrhea, macular rash and abdominal pain with acute renal failure leading to end-stage kidney disease. Laboratory results showed hematuria, nephrotic range proteinuria, worsening creatinine and low C1q levels. Left kidney biopsy showed proliferative glomerulonephritis with crescent formation. She was treated with 6 months of intravenous cyclophosphamide, followed by 2 doses of intravenous rituximab (1g each), thereafter maintained on mycophenolate mofetil and glucocorticoid-based therapy. She experienced a full recovery of renal function after 12 months of dialysis dependence. Hypocomplementemic urticarial vasculitis syndrome with crescentic glomerulonephritis is a rare disease with only 5 other reported cases in literature. In our case, we document a delayed but excellent renal recovery during a 2-year follow-up.

Topics: Adult; Complement C1q; Cyclophosphamide; Female; Glomerulonephritis, Membranoproliferative; Hematuria; Humans; Kidney Failure, Chronic; Mycophenolic Acid; Proteinuria; Rituximab; Syndrome; Urticaria; Vasculitis

Standard induction therapy for lupus nephritis (LN) with mycophenolate mofetil (MMF) or cyclophosphamide (CYC) is often ineffective. Evidence on rescue induction regimens is scarce. We analyzed efficacy and tolerability of multitarget immunosuppression with MMF and cyclosporine A (CsA) as induction treatment for LN (class III/IV/V) refractory to CYC and/or MMF. We included all six refractory LN patients (class IV = 3, class V = 2, class III = 1) from our 400-patient tertiary Lupus Clinic observed between 2012 and 2015. Four patients had previously received pulse CYC. All six received MMF as first or second induction therapy and CsA was added once failure to reach remission was established. Daily dose of MMF was 2-3 g and CsA was dosed up to 2.6-3.7 mg/kg/day. Mean proteinuria was reduced from 2407 mg/24 hours at the start of the MMF+CsA regimen to 544 mg/day after six months. The mean prednisolone dose was reduced from 17.5 to 6 mg/day after six months of MMF+CsA. Four patients achieved a complete renal response, one patient had a partial renal response and one failed to respond. None of the patients presented with adverse events. These data suggest that adding CsA to MMF can induce complete remission of refractory LN and is well tolerated.

Topics: Adult; Cyclophosphamide; Cyclosporine; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Kidney; Lupus Nephritis; Middle Aged; Mycophenolic Acid; Portugal; Prednisolone; Proteinuria; Remission Induction; Retrospective Studies; Young Adult

To compare renal outcomes between cyclophosphamide (CYC) and mycophenolate mofetil (MMF), and attempt to identify a predictor of renal survival.. A total of 99 patients with class III-V lupus nephritis (LN) and treated with CYC or MMF were enrolled. The remission rate and predictors of poor renal outcomes in LN were assessed.. The mean age at LN diagnosis was 31.7 years. The baseline characteristics of the two groups were similar except for the chronicity index (3.1 ± 2.4 and 2.3 ± 0.8 for CYC and MMF, respectively, P = 0.007). The overall remission rate was 76.8% and 77.7% after 6 and 12 months, respectively, with no significant difference between the two groups at these time points. After a median follow-up of 36 months (interquartile range 12-60), eight (8.1%) patients had chronic kidney disease, four (4.1%) were dialyzed permanently, and seven (7.1%) suffered a relapse, with no significant difference in these final outcomes between the two groups. Adverse events included infection (CYC group), and rash and neutropenia (MMF group), with no significant difference in frequency between the two groups. Failure of induction therapy (hazards ratio [HR] = 10.626, P = 0.022) and the creatinine level at diagnosis of LN (HR = 8.397, P = 0.007) were significantly associated with renal survival adjusted for age at LN diagnosis, disease duration and proteinuria.. Response to current induction therapy for LN was favorable, and 6 months response following induction therapy was the most important predictor for renal survival.

Topics: Adolescent; Adult; Cyclophosphamide; Disease Progression; Female; Humans; Immunosuppressive Agents; Kidney; Lupus Nephritis; Male; Mycophenolic Acid; Proteinuria; Recurrence; Remission Induction; Renal Dialysis; Renal Insufficiency, Chronic; Republic of Korea; Risk Factors; Time Factors; Treatment Outcome; Young Adult

Morphological change that includes diffuse effacement of podocyte foot processes is correlated with proteinuria in patients with lupus nephritis (LN). We collected the data of clinico-pathological parameters and assessed foot process width (FPW) as an index of podocyte effacement in 73 patients with LN who had undergone renal biopsy. The multivariate analysis revealed that female gender (OR: 5.288; 95%CI: 1.197-37.29; p = .0267) and FPW (OR = 0.999, 95%CI = 0.997-0.999, p = .0150) were significantly predictive of a complete renal response (CR) at 6 months, while lymphocyte counts (OR = 1.002; 95%CI = 1.001-1.003, p = .0028) and FPW (OR = 0.998, 95%CI = 0.996-0.999, p = .0027) were significantly predictive of CR at 12 months. The cut-off point determined by the Classification and Regression Trees algorithm showed that FPW <908.3 nm provides the best performance for predicting patients who achieve CR at 12 months. A smaller FPW appears to be a predictive factor for CR at 6 and 12 months after induction therapy.

Topics: Adult; Creatinine; Cyclophosphamide; Cyclosporine; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Logistic Models; Lupus Nephritis; Male; Methylprednisolone; Middle Aged; Multivariate Analysis; Mycophenolic Acid; Podocytes; Prednisolone; Prognosis; Proteinuria; Remission Induction; Retrospective Studies; Severity of Illness Index; Tacrolimus

BACKGROUND The most appropriate management of Henoch-Schönlein Purpura (HSP) nephritis with nephrotic-range proteinuria remains uncertain. The aim of this study was to evaluate the clinical therapeutic effects of mycophenolate mofetil and low-dose steroid in Henoch-Schönlein purpura nephritis (HSPN) with nephrotic-range proteinuria and pathological classification less than IV in children. MATERIAL AND METHODS The clinical effects of MMF and low-dose steroid therapy were studied in children with Henoch-Schönlein purpura nephritis manifested with nephrotic-range proteinuria, normal kidney function, and <50% crescents or sclerosing lesions on renal biopsy. We enrolled 32 boys and 29 girls with nephrotic-range proteinuria, normal kidney function, and pathological classification less than IV on renal biopsy. We treated 41 cases (67.2%) with mycophenolate mofetil and low-dose prednisone combined therapy and 20 cases (32.8%) were treated with full-dose prednisone alone. RESULTS Short-term response was significantly different between 2 groups (χ²=4.371, P=0.037), while no significant difference was found in long-term prognosis (χ²=0.419, P=0.522) after follow-up. The ROC curve showed that the most appropriate cutoff value was 30.67 μg·h/ml for MPA-AUC and the area under the ROC curve was 0.731, with 85.2% sensitivity and 64.3% specificity. CONCLUSIONS Mycophenolate mofetil and low-dose prednisone combined therapy is a reasonable treatment choice which can promote the remission of proteinuria without increasing obvious adverse reactions in pediatric HSPN with nephrotic state and pathological classification less than grade IV. MPA-AUC more than 30 μg·h/ml was an appropriate value for MMF in the combined therapy with MMF and steroid for treating children with HSPN.

Topics: Biopsy; Child; Child, Preschool; China; Drug Therapy, Combination; Female; Glomerulonephritis; Humans; IgA Vasculitis; Immunosuppressive Agents; Kidney; Male; Mycophenolic Acid; Nephritis; Prednisone; Proteinuria; Retrospective Studies; ROC Curve; Steroids

IgA nephropathy (IgAN) is the most common primary glomerulonephritis in developed countries and a leading cause of chronic kidney disease. IgAN is a mesangial proliferative glomerulonephritis characterized by diffuse mesangial deposition of IgA, often accompanied by the deposition of IgG and the C3 component of complement in a similar distribution. This condition is in most cases oligosymptomatic, often discovered coincidentally. Currently, there is no specific treatment available for IgAN and the use of immunosuppression therapy is debated. Due to immune-mediated pathogenic nature of IgAN, therapy with mycophenolate mofetil (MMF), a potent immunosuppressive agent, could be effective in patients at risk for progressive disease. In this paper, we discuss the case of an IgAN patient treated with MMF at our center, followed by a review of the literature and our previous experience on the potential renoprotective effects of MMF in IgAN patients with different clinical presentation, despite adequate angiotensin blockade and steroid therapy.

Topics: Adult; Glomerulonephritis, IGA; Humans; Immunosuppressive Agents; Male; Mycophenolic Acid; Proteinuria; Treatment Outcome

Hemophagocytic lymphohistiocytosis is an aggressive life-threatening syndrome of excessive immune activation. Hemophagocytic lymphohistiocytosis due to systemic lupus erythematosus is described as acute lupus hemophagocytic syndrome. Acute lupus hemophagocytic syndrome presenting with negative antinuclear antibody is uncommon.. A 57-year-old Sri Lankan woman presented with intermittent fever, weight loss, episodic confusion, and alopecia for 3 months. Investigations showed pancytopenia. Her erythrocyte sedimentation rate was 76 mm/hour and C-reactive protein was 2 mg/l. Septic screen was negative except for a positive sputum culture for Gram-negative coliforms. Chest X-ray was normal. Direct antiglobulin test was positive. Fever persisted with clinical worsening despite treatment with intravenous antibiotics. Antinuclear antibodies and double-stranded-deoxyribonucleic acid antibodies were negative. Bone marrow aspiration revealed features compatible with hemophagocytosis. Her serum ferritin and triglycerides were elevated. Diagnosis of hemophagocytic lymphohistiocytosis due to an evolving autoimmune disorder was made and she was treated with steroids. She showed a dramatic improvement and was discharged on oral steroids. After 6 months, while the steroids were being tapered she experienced oral ulcers, frothy urine, and ankle swelling and she was rehospitalized. Urine analysis revealed proteinuria with active sediment. Antinuclear antibodies and double-stranded-deoxyribonucleic acid antibodies were positive. Complement C3 and C4 were reduced. A renal biopsy revealed class IV-G lupus nephritis with immunofluorescence pattern consistent with systemic lupus erythematosus. Steroid dose was increased and mycophenolate mofetil was commenced. She improved.. This case showcases an uncommon presentation of acute lupus hemophagocytic syndrome with initial negative antinuclear antibody probably due to its cytokine-mediated pathogenesis. This is the first such reported case in South Asia to the best of our knowledge. According to the American College of Rheumatology criteria, our patient did not fulfill the criteria for systemic lupus erythematosus diagnosis for the initial hospitalization. But, according to the 2012 Systemic Lupus International Collaborating Clinics criteria, she did fulfill the criteria for systemic lupus erythematosus even in the first hospitalization which was subsequently proven with renal biopsy findings. This case confirms the increased sensitivity of Systemic Lupus International Collaborating Clinics criteria over American College of Rheumatology criteria in diagnosis of systemic lupus erythematosus.

Topics: Alopecia; Confusion; Female; Fever; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Lymphohistiocytosis, Hemophagocytic; Middle Aged; Mycophenolic Acid; Pancytopenia; Proteinuria; Steroids; Treatment Outcome; Weight Loss

In progressive immunoglobulin (Ig)A nephropathy (IgAN), cyclophosphamide pulse therapy (CyP), high-dose intravenous immunoglobulins (IVIg) and mycophenolic acid (MPA) have been used to stop progressive loss of renal function, but disease progression may occur after the end of the initial treatment. Here, we report the long-term follow-up of patients with progressive IgAN with MPA as maintenance therapy after CyP (CyP-MPA). In a median observation time of 6·2 years, we analysed the slopes of the loss of renal function of 47 patients with biopsy-proven IgAN and treated with CyP. Thirty-one patients with further progression were treated with MPA maintenance for a median time of 5·2 years. Follow-up was compared with symptomatic therapy and IVIg as historically matched control groups. Median loss of renal function was reduced significantly from 0·9 ml/min to 0·1 ml/min per month with CyP (P < 0·05), and with MPA in patients with a relapse from -0·4 ml/min to -0·1 ml/min per month (P < 0·05) until the end of the study. Proteinuria decreased significantly from 1·6 g/l to 1·0 g/l after CyP, and during MPA treatment to 0·6 g/l (P = 0·001 Friedman test). Median renal survival time was in patients with CyP 10·5 years (range = 3·2-17·8), with CyP-MPA 10·7 years (range = 8·3-13·1), with IVIg 4·7 years (range = 2·6-6·6), and in untreated patients 1·2 years (range = 0·8-1·6; log-rank test P < 0·01). In patients with progressive IgAN, our long-term follow-up observation indicates that sequential CyP-MPA therapy maintains renal survival significantly.

Topics: Adult; Aged; Cyclophosphamide; Disease Progression; Follow-Up Studies; Glomerulonephritis, IGA; Humans; Immunosuppressive Agents; Kidney; Maintenance Chemotherapy; Male; Middle Aged; Mycophenolic Acid; Proteinuria; Risk Factors

To uniquely classify children with microscopic polyangiitis (MPA), to describe their demographic characteristics, presenting clinical features, and initial treatments in comparison to patients with granulomatosis with polyangiitis (Wegener's) (GPA).. The European Medicines Agency (EMA) classification algorithm was applied by computation to categorical data from patients recruited to the ARChiVe (A Registry for Childhood Vasculitis: e-entry) cohort, with the data censored to November 2015. The EMA algorithm was used to uniquely distinguish children with MPA from children with GPA, whose diagnoses had been classified according to both adult- and pediatric-specific criteria. Descriptive statistics were used for comparisons.. In total, 231 of 440 patients (64% female) fulfilled the classification criteria for either MPA (n = 48) or GPA (n = 183). The median time to diagnosis was 1.6 months in the MPA group and 2.1 months in the GPA group (ranging to 39 and 73 months, respectively). Patients with MPA were significantly younger than those with GPA (median age 11 years versus 14 years). Constitutional features were equally common between the groups. In patients with MPA compared to those with GPA, pulmonary manifestations were less frequent (44% versus 74%) and less severe (primarily, hemorrhage, requirement for supplemental oxygen, and pulmonary failure). Renal pathologic features were frequently found in both groups (75% of patients with MPA versus 83% of patients with GPA) but tended toward greater severity in those with MPA (primarily, nephrotic-range proteinuria, requirement for dialysis, and end-stage renal disease). Airway/eye involvement was absent among patients with MPA, because these GPA-defining features preclude a diagnosis of MPA within the EMA algorithm. Similar proportions of patients with MPA and those with GPA received combination therapy with corticosteroids plus cyclophosphamide (69% and 78%, respectively) or both drugs in combination with plasmapheresis (19% and 22%, respectively). Other treatments administered, ranging in decreasing frequency from 13% to 3%, were rituximab, methotrexate, azathioprine, and mycophenolate mofetil.. Younger age at disease onset and, perhaps, both gastrointestinal manifestations and more severe kidney disease seem to characterize the clinical profile in children with MPA compared to those with GPA. Delay in diagnosis suggests that recognition of these systemic vasculitides is suboptimal. Compared with adults, initial treatment regimens in children were comparable, but the complete reversal of female-to-male disease prevalence ratios is a provocative finding.

Topics: Adolescent; Adrenal Cortex Hormones; Age Distribution; Antibodies, Antineutrophil Cytoplasmic; Asia; Azathioprine; Canada; Child; Child, Preschool; Cohort Studies; Cyclophosphamide; Drug Therapy, Combination; Europe; Female; Granulomatosis with Polyangiitis; Hemorrhage; Humans; Immunosuppressive Agents; Infant; Kidney Failure, Chronic; Lung Diseases; Male; Methotrexate; Microscopic Polyangiitis; Mycophenolic Acid; Nephrotic Syndrome; Oxygen Inhalation Therapy; Plasmapheresis; Proteinuria; Renal Dialysis; Respiratory Insufficiency; Rituximab; United States

Kimura's disease (KD) with renal involvement is a rare disease. Optimal treatments are still not well established. It is necessary to analyze clinicopathological features, treatment responses, and prognosis for improving KD diagnosis and treatment.. Clinicopathological data, treatment responses, and prognosis were collected and analyzed retrospectively.. The patients consisted of 27 males and 2 females, with an average age of 35.5 ± 15.1 (13 - 61) years. 27 exhibited proteinuria ranging from 0.730 to 14.1 g/24 h (5.98 ± 3.40 g/24 h). Hypertension, renal insufficiency (serum creatinine (Scr) > 1.24 mg/dL), and microhematuria occurred in 4 (13.8%), 11 (37.9%), and 13 (44.8%) cases, respectively. Light microscopy (LM) identified mesangium proliferation, minimal change, focal and segmental glomerulosclerosis (FSGS), membranous glomerulonephritis, membranoproliferative glomerulonephritis (MPGN), and acute tubular necrosis in 14, 8, 3, 2, 1, and 1 cases, respectively. All were treated with Tripterygium wilfordii (TW), prednisone, leflunomide (LEF), tacrolimus (FK506), myophenolate mofetil (MMF), or renin-angiotensin system blockers (RASI). 26 patients were followed up for 1.60 - 108.7 months (39.6 ± 28.7). After treatments, urinary red blood cells (RBC) decreased in all. The amount of 24-hour urinary protein (24-hUPE) decreased in 24 patients. 22 reached complete remission (CR), 4 partial remissions (PR). The patients who did not relapse were younger than those who relapsed.. KD with renal involvement occurs predominantly among 35 - 50 year old Chinese patients with male predilection. The most common features are proteinuria, hypertension, micro hematuria with minimal change, and mesangial proliferative glomerulonephritis. Most were responsive to treatment, but could relapse. Gender, age, and hypertension are associated with KD recurrence. The prognosis is good mostly.

Topics: Adolescent; Adult; Angiolymphoid Hyperplasia with Eosinophilia; Anti-Inflammatory Agents; China; Female; Glomerulonephritis; Glomerulonephritis, Membranoproliferative; Glomerulonephritis, Membranous; Glomerulosclerosis, Focal Segmental; Hematuria; Humans; Hypertension; Immunosuppressive Agents; Isoxazoles; Leflunomide; Male; Middle Aged; Mycophenolic Acid; Phytotherapy; Plant Preparations; Prednisone; Prognosis; Proteinuria; Recurrence; Renal Insufficiency; Retrospective Studies; Tacrolimus; Tripterygium; Young Adult

To assess the effectiveness and safety of the conversion therapy from traditional cyclosporine (CsA) triple immunosuppression therapy to sirolimus (SRL) combined with low dose CsA and prednisone (Pred) in renal transplantation recipients in a five-year follow-up period.. A prospective, open-label non-randomized study was performed with 46 renal allograft recipients who visited Tongji Hospital regularly for follow-up visits between January 2007 and May 2011 and were taking CsA+ mycophenolate mofetil (MMF)+ Pred. Conversion therapy to SRL+ low dose CsA+ Pred was initiated after renal transplantation. The recipients were allocated to 2 groups according to their renal function and proteinuria before the conversion: active conversion group [n=27, serum creatinine (SCr) ≤ 140 μmol/L with no or minimal proteinuria] and passive conversion group [n=19, SCr>140 μmol/L with less than moderate proteinuria]. After conversion, dosages of SRL and CsA were adjusted for trough levels of 5-7 μg/L and 20-60 μg/L, respectively. SCr and urine protein were compared before and after the conversion in five-year follow-up. Incidence of acute rejection, renal graft survival and SRL-related adverse effects of the immunosuppressive regimen were also observed.. After conversion, an average 63% dose reduction of CsA was achieved in all the patients. In the active conversion group, the mean SCr level was (110±19) μmol/L at the time of conversion. Eight patients in this group withdrew from the study during the follow-up period for the following reasons: arthralgia (1 case), deteriorated proteinuria (2 cases), chronic diarrhea (2 cases), mild or suspicious acute rejection (2 cases), and recurrent fever (1 case). The rest patients (19/27) with a mean follow-up time of 5 years had a stable SCr level [(103±12) μmol/L] and a 100% 5-year graft survival. In the passive conversion group, the mean SCr level was (205±45) μmol/L at the time of conversion. There were 4 patients quitting the study, 2 for deteriorated proteinuria and 2 for lost to follow-up. Chronic allograft failure developed in 10 patients in this group 1-50 months after conversion, while the remaining 5 patients had a stable SCr during the 5-year follow-up period [(218 ±46) μmol/L before conversion vs (205±73) μmol/L 5 years after conversion]. The overall 5-year graft survival after the conversion therapy in the passive conversion group was 33.3%, significantly lower than that of the active conversion group (P<0.001). Acute rejection was observed in 2 cases in the active conversion group, while not observed in the passive conversion group. None of the patients developed leukopenia, thrombocytopenia, oral ulcer, or pneumonia in the follow-up.. The combination therapy of SRL and low dose of CsA is overall a safe and effective maintenance immunosuppressive regimen, but it is important to initiate at an appropriate stage. More favourable long-term benefits may be obtained from the conversion therapy in patients with normal or only slightly impaired renal graft function. It may offer an option of individualized immunosuppressive therapy after renal transplantation.

Topics: Adult; Cyclosporine; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney; Kidney Transplantation; Male; Mycophenolic Acid; Prednisone; Prospective Studies; Proteinuria; Sirolimus; Transplantation, Homologous

Over a period of 3 years (January 2011 to December 2013) 100 cases of Lupus nephritis patients admitted in nephrology department of Bangabandhu Sheikh Mujib Medical University (BSMMU) were evaluated. Their clinical characteristics, biochemical parameters, renal histology according to WHO classification were categorized and their treatment modalities and outcome was observed. Among 100 patients, 84 were female and 16 were male, with F:M ratio 5:1. Mean age of female were 23±4 years and male were 29±4 years, mean BP in male was systolic 135±8 mmHg, diastolic 80±9mmHg and in female systolic was 130±7mmHg, diastolic 75±6 mmHg, mean Serum Creatinine for male was 180±12μmol/L and mean serum creatinine in female was 170±20μmol/L. Sixty five percent (65%) patient showed extra renal manifestation. All patients presented with proteinuria, among them 45% were nephrotic presentation, 25% patients presented with acute nephritic illness, 15% were nephritic nephrotic, 10% patients had rapidly progressing glomerulonephritis (RPGN), and 5% were with asymptomatic proteinuria. Renal biopsy of 100 patient according to WHO classification showed class I - 5%, class II - 20%, class III - 26%, class IV - 35%, class V - 8%, class VI - 6%. Immunosuppressive protocol used was prednisolone and cyclophorphamide in the majority of patients in class III to class VI LN patients. Few patients received prednisolone and mycophenolate mofetil. Twenty four percent (24%) patients were in complete remission during this study period and 12% developed end stage renal disease (ESRD). Seventy six percent (76%) patients passed through various stages of CKD, majority of them were in CKD stage IV and stage III, and few were in CKD stage I and stage II. About 70% of the participants had suffered from one or more complications, where majority were infections. Infections and renal failure were the leading cause of death in our study.

Topics: Adolescent; Adult; Bangladesh; Cyclophosphamide; Female; Humans; Immunosuppressive Agents; Lupus Nephritis; Male; Mycophenolic Acid; Prednisolone; Prospective Studies; Proteinuria; Remission Induction; Treatment Outcome; Young Adult

The clinic-pathological features and outcomes of Chinese patients with antineutrophil cytoplasmic autoantibody (ANCA)-positive eosinophilic granulomatosis with polyangiitis (EGPA) and renal involvement have not been studied.. Fourteen EGPA patients with renal involvement were included. All patients underwent renal biopsy. Clinic-pathological features and outcomes were retrospectively analyzed.. The most common initial symptom of EGPA was asthma (57.1 %), followed by hemoptysis (21.4 %), gross hematuria (14.3 %), and arthritis (7.1 %). All patients had positive serum ANCA (anti-MPO in 12, anti-PR3 in 2). Elevated eosinophils (median 15 %, range 10-45 %) were found in all patients. The median serum IgE level was 463 g/L (range 200-1000 g/L). All patients presented with renal dysfunction, with a median SCr of 5.4 mg/dL (range 1.47-11 mg/dL), seven patients (50 %) required initial renal replacement therapy. Thirteen patients showed hematuria and proteinuria (median 1.1 g/24 h, range 0.5-7.8 g/24 h). Renal biopsy showed pauci-immune segmental necrotizing glomerulonephritis with crescents in 13 patients and acute interstitial nephritis in one patient. Twelve patients (85.7 %) showed renal interstitial eosinophil infiltration, among whom three had eosinophilic granuloma. Among seven patients (71.4 %) who required initial dialysis, 5 discontinued dialysis, one died, one received maintenance dialysis after glucocorticoids plus immunosuppressive for induction treatment. Twelve patients were followed up for a median of 43.5 months (range 6-83 months), during follow-up, two patients progressed to end-stage renal disease, nine had chronic kidney disease with eGFR < 60 mL/min, and two patients had normal eGFR.. Renal involvement in ANCA-positive EGPA could be severe and showed varied renal histology. Although intensive immunosuppressive therapy effectively improved the renal function, the long-term renal survival was poor. Early diagnosis and treatment are essential to improve long-term renal survival.

Topics: Adolescent; Adult; Aged; Anti-Inflammatory Agents; Antibodies, Antineutrophil Cytoplasmic; Blood Cell Count; China; Churg-Strauss Syndrome; Creatinine; Cyclophosphamide; Disease Progression; Drug Therapy, Combination; Eosinophils; Female; Glomerular Filtration Rate; Hematuria; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Male; Methylprednisolone; Middle Aged; Mycophenolic Acid; Prednisone; Proteinuria; Renal Dialysis; Renal Insufficiency, Chronic; Retrospective Studies; Time Factors; Young Adult

Lupus nephritis (LN) is one of the most severe manifestations of systemic lupus erythematosus (SLE), affecting ∼50% of patients, and both renal disease and treatment-related toxicity contribute to significant morbidity and mortality. Although our understanding of the aetiopathogenesis of LN is improving, treatment still remains a challenge, with the achievement of complete remission at 1 year in <50% of patients treated with current standard of care immunosuppressive therapy; this is associated with considerable short- and long-term side effects, some of which further contribute to non-adherence. Calcineurin inhibitors (CNIs) have been successfully used in organ transplantation and there is increasing evidence that cyclosporin A (CSA), and especially tacrolimus (TAC), are also effective in the treatment of LN. Randomised controlled trials showed similar efficacy for TAC when compared with mycophenolate mofetil (MMF) and multitarget therapy, including TAC and low-dose MMF, and resulted in significantly more complete remissions and overall responses compared with intravenous cyclophosphamide (CYC). Flares are observed in up to 45% of patients with LN, and an increase in relapse rate following induction with CNIs may be an issue. Most studies on this matter have been restricted to patients from Asia, and studies in more balanced cohorts are desirable. Moreover, there is a need to understand and determine the long-term effects of CNIs on renal function, proteinuria and comorbidities, with a special focus on cardiovascular risk. In this 'Pros and Cons' debate, the potential benefits and disadvantages of CNIs in the treatment of LN will be critically highlighted.

Topics: Calcineurin Inhibitors; Cardiovascular Diseases; Cyclophosphamide; Cyclosporine; Humans; Immunosuppressive Agents; Lupus Nephritis; Maintenance Chemotherapy; Mycophenolic Acid; Proteinuria; Risk Factors; Tacrolimus

Topics: Adult; Cyclosporine; Female; Glomerulosclerosis, Focal Segmental; Humans; Immunologic Factors; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Nephrotic Syndrome; Proteinuria; Receptors, Urokinase Plasminogen Activator; Recurrence; Rituximab; Tacrolimus

Topics: Adaptive Clinical Trials as Topic; Adult; Child; Clinical Trials as Topic; Cyclosporine; Disease Progression; Glomerular Filtration Rate; Glomerulosclerosis, Focal Segmental; Glucocorticoids; Humans; Immunosuppressive Agents; Mycophenolic Acid; Nephrotic Syndrome; Patient Reported Outcome Measures; Proteinuria; Research Design

There are very little data available regarding nephrotic syndrome (NS) in elderly (aged ≥65 years) Japanese. The aim of this study was to examine the causes and outcomes of NS in elderly patients who underwent renal biopsies between 2007 and 2010.. From July 2007 to June 2010, all of the elderly (aged ≥65 years) Japanese primary NS patients who underwent native renal biopsies and were registered in the Japan renal biopsy registry (J-RBR; 438 patients including 226 males and 212 females) were identified. From this cohort, 61 patients [28 males and 33 females including 29, 19, 6, 4, and 3 patients with membranous nephropathy (MN), minimal change nephrotic syndrome (MCNS), focal segmental glomerulosclerosis (FSGS), membranoproliferative glomerulonephritis (MPGN), and other conditions, respectively] were registered from the representative multi-centers over all districts of Japan, and analyzed retrospectively. The treatment outcome was assessed using proteinuria-based criteria; i.e., complete remission (CR) was defined as urinary protein level of <0.3 g/day or g/g Cr, and incomplete remission type I (ICR-I) was defined as urinary protein level of <1.0-0.3 g/day or g/g Cr, and renal dysfunction was defined as a serum creatinine (Cr) level of 1.5 times the baseline level.. In this elderly primary NS cohort, MN was the most common histological type of NS (54.8 %), followed by MCNS (19.4 %), FSGS (17.4 %), and MPGN (8.4 %). Of the patients with MN, MCNS, or FSGS, immunosuppressive therapy involving oral prednisolone was performed in 25 MN patients (86.2 %), 18 MCNS patients (94.7 %), and all 6 FSGS patients (100 %). CR was achieved in all 19 (100 %) MCNS patients. In addition, CR and ICR-I were achieved in 16 (55.2 %) and 18 (62.1 %) MN patients and 4 (66.7 %) and 5 (83.3 %) FSGS patients, respectively. There were significant differences in the median time to CR among the MCNS, FSGS, and MN patients (median: 26 vs. 271 vs. 461 days, respectively, p < 0.001), and between the elderly (65-74 years, n = 7) and very elderly (aged ≥75 years, n = 12) MCNS patients (7 vs. 22 days, p = 0.037). Relapse occurred in two (6.9 %) of the MN and nine (47.4 %) of the MCNS patients. Renal dysfunction was observed in five (7.2 %) of the MN patients. Serious complications developed in eight (14.8 %) patients, i.e., two (3.7 %) patients died, four (7.4 %, including three MCNS patients) were hospitalized due to infectious disease, and two (3.7 %) developed malignancies. The initiation of diabetic therapy was necessary in 14 of the 61 patients (23.0 %) with much higher initial steroid dosage.. Renal biopsy is a valuable diagnostic tool for elderly Japanese NS patients. In this study, most of elderly primary NS patients respond to immunosuppressive therapy with favorable clinical outcomes. On the other hand, infectious disease is a harmful complication among elderly NS patients, especially those with MCNS. In future, modified clinical guidelines for elderly NS patients should be developed.

Topics: Aged; Aged, 80 and over; Biopsy; Creatinine; Cyclophosphamide; Cyclosporine; Female; Follow-Up Studies; Glomerulonephritis; Glomerulonephritis, Membranoproliferative; Glomerulonephritis, Membranous; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Japan; Kidney; Male; Methylprednisolone; Mycophenolic Acid; Nephrosis, Lipoid; Nephrotic Syndrome; Prednisolone; Proteinuria; Recurrence; Registries; Retrospective Studies; Ribonucleosides; Treatment Outcome

The objective of this study is to determine the predictive risk factors of failure to achieve remission within 12 months in a group of patients with proliferative lupus nephritis from Northwestern Colombia. Pragmatic clinical study with retrospective analysis was conducted. We included subjects with systemic lupus erythematosus as defined by the American College of Rheumatology with biopsy-proven nephritis. We assessed 149 patients, with 84 % female. Age at diagnosis of systemic lupus erythematosus is 24.7 years (16-31). The time between diagnosis of lupus erythematosus and proliferative nephritis is 2 months (0-35.5). ISN/RPS 2003 histologic classification types are the following: IV (63.8 %), III (13.4 %), V + III (3.3 %), and V + IV (3.3 %). Activity index is 6.18 ± 4.55 and chronicity index is 1 (0-3). The result of 24-h proteinuria is 2000 mg (667-4770) and baseline creatinine is 0.9 mg/dL (0.7-1.3). Induction therapy includes corticosteroids (100 %), cyclophosphamide (74.1 %), and mycophenolate mofetil (25.9 %). At 12 months, 40.7 % of individuals failed to attain partial or complete remission. Elevated creatinine (p = 0.0001) and 24-h proteinuria greater than 1500 mg (p = 0.0011) were basal predictors of failure to attain partial or complete remission by bivariate analysis. Similar results were obtained in multivariate analysis: Baseline creatinine elevation (OR 3.62, 95 % CI, 1.59-8.23; p = 0.002) and 24-h proteinuria greater than 1500 mg (OR 3.62, 95 % CI, 1.29-10.13; p = 0.014) were independent predictors of failure to achieve partial or complete remission. At 12 months, 40.7 % of patients did not attain partial or complete remission. Baseline elevated creatinine and 24-h proteinuria over 1500 mg were predictors for poor response.

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Cohort Studies; Colombia; Creatinine; Cyclophosphamide; Female; Humans; Immunosuppressive Agents; Indians, South American; Lupus Nephritis; Male; Mycophenolic Acid; Prognosis; Prospective Studies; Proteinuria; Remission Induction; Retrospective Studies; Risk Factors; Severity of Illness Index; Treatment Outcome; Young Adult

Recently, the mammalian target of rapamycin inhibitor everolimus (EVL) has been introduced as a novel immunosuppressant for heart transplant (HTx) recipients, and is expected to preserve renal function compared to conventional calcineurin inhibitors (CNIs). However, a considerable number of recipients treated with EVL were not free from worsening renal function regardless of CNI reduction. Data were collected retrospectively from 27 HTx recipients who had received EVL (trough concentration, 3.1-9.2 ng/mL) along with reduced CNIs (%decreases in trough concentration, 27.3 ± 13.0%) because of switching from mycophenolate mophetil due to digestive symptoms or neutropenia, progressive coronary artery vasculopathy, or persistent renal dysfunction, and had been followed over 1 year between August 2008 and January 2013. Estimated glomerular filtration rate (eGFR) decreased in 5 recipients (18.5%) during the study period. Univariate logistic regression analysis demonstrated that a higher plasma neutrophil gelatinase-associated lipocalin (P-NGAL) level was the only significant predictor for a decrease in eGFR over a 1-year EVL treatment period among all baseline parameters (P = 0.008). eGFR and proteinuria worsened almost exclusively in patients with baseline P-NGAL ≥ 85 ng/mL, which was the cutoff value calculated by an ROC analysis (area under the curve, 0.955; sensitivity, 1.000; specificity, 0.955). In conclusion, higher P-NGAL may be a novel predictor for the worsening of renal function after EVL treatment that is resistant to CNI reduction in HTx recipients.

Topics: Acute-Phase Proteins; Adult; Dose-Response Relationship, Drug; Drug Monitoring; Everolimus; Female; Glomerular Filtration Rate; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Japan; Lipocalin-2; Lipocalins; Male; Middle Aged; Mycophenolic Acid; Predictive Value of Tests; Prognosis; Proteinuria; Proto-Oncogene Proteins; Renal Insufficiency; Retrospective Studies; ROC Curve; Sirolimus

Immunoglobulin A nephropathy (IgAN) presents as nephrotic syndrome (NS) relatively rarely, and the current treatment experience of IgAN patients with NS is mostly with adults. The objective of our study was to investigate the efficacy of corticosteroids and mycophenolate mofetil (MMF) in treating childhood immunoglobulin A nephropathy (IgAN) with nephrotic syndrome.. A total of 58 children (39 boys and 19 girls) diagnosed with nephrotic syndrome and primary IgAN were enrolled in the study. All the patients were administered prednisone 2 mg/kg per day for 8 weeks. Steroid-resistant patients were treated with the combined use of MMF (dose of 20 ~ 30 mg/kg per day) and prednisone for 6-12 months. The prednisone dose was reduced stepwise during the combined treatment.. Of the 58 children, 14 were steroid-sensitive (M, S, and T variants of the Oxford classification were 0 in most children), and 44 cases who presented serious pathological damage to the kidney were steroid-resistant. The estimated glomerular filtration rate (eGFR) of the steroid-resistant children (86.69 ± 26.85 ml/min/1.73 m(2)) was significantly lower (P < 0.05) than that of the steroid-sensitive children (106.89 ± 26.94 ml/min/1.73 m(2)). After 4 months of combined MMF treatment in 33 steroid-resistant children, complete remission of proteinuria was found in 21 cases, partial remission of proteinuria in 6 cases, and no response was found in 6 cases. Except for the T variant, other variants of the Oxford classification, including M, E, and S morphological variables, was not significantly different among patients complete remission, those with partial remission, and those with no response. The eGFR of children with complete remission of proteinuria (100.04 ± 18.47 ml/min/1.73 m(2)), that of those with partial remission (92.24 ± 27.63 ml/min/1.73 m(2)), and that of those with no response (72.17 ± 27.55 ml/min/1.73 m(2)) were significantly different (P < 0.05).. Corticosteroid therapy showed satisfactory efficacy in IgAN children with nephrotic syndrome and slight pathological damage. The effect of MMF was good for steroid-resistant IgAN children, but poor for those with tubular atrophy/interstitial fibrosis and renal function impairment.

Topics: Adrenal Cortex Hormones; Anti-Inflammatory Agents, Non-Steroidal; Biopsy; Child; Child, Preschool; Drug Resistance; Female; Follow-Up Studies; Glomerular Filtration Rate; Glomerulonephritis, IGA; Humans; Immunosuppressive Agents; Kidney; Male; Mycophenolic Acid; Nephrotic Syndrome; Prednisone; Prospective Studies; Proteinuria; Treatment Outcome

Lupus podocytopathy is a newly recognized class of lupus nephritis characterized by extensive glomerular foot process effacement without capillary wall immune deposits. The treatment response and relapse of glucocorticoid with or without additional immunosuppressive agents has not been well investigated. In this study, 50 patients with lupus podocytopathy were included and received glucocorticoid alone (glucocorticoid monotherapy) or glucocorticoid plus additional immunosuppressive agents (combination therapy) for their induction or maintenance treatment regimens. The treatment response and relapse rate in the two groups were respectively analyzed. We found that the induction treatment with glucocorticoid monotherapy and combination therapy led to remission in 47 patients (94.0%) at 12 weeks treatment, with complete remission (CR) occurring in 38 patients (76.0%). The CR rate compared between glucocorticoid monotherapy and combination therapy showed no difference (76.7% vs 75.0%, p = 0.9), the median time to CR was four weeks (range: 2.0-6.0 weeks) in glucocorticoid monotherapy and 8.0 weeks (range: 3.7-12.0 weeks) in combination therapy (p = 0.076). Twenty-seven of 47 patients (57.4%) relapsed during maintenance, the relapse rate was much higher in the glucocorticoid monotherapy group than in the combination therapy group (89.5% vs 35.7%, p < 0.001), regardless of the induction regimens being glucocorticoid monotherapy or combination therapy. No patient developed end stage renal disease or died during follow-up for 6-125 months (median 62 months). In conclusion, the remission of lupus podocytopathy could be induced by glucocorticoid monotherapy or glucocorticoid plus other immunosuppressive agents, while the remission should be maintained by the combination regimen.

Topics: Adolescent; Adult; Azathioprine; Cyclophosphamide; Drug Therapy, Combination; Female; Follow-Up Studies; Glucocorticoids; Humans; Immunosuppressive Agents; Isoxazoles; Kidney; Leflunomide; Lupus Nephritis; Male; Mycophenolic Acid; Nephrotic Syndrome; Podocytes; Prednisone; Proteinuria; Remission Induction; Retrospective Studies; Tacrolimus; Treatment Outcome

BK viremia and polyomavirus-associated nephropathy (PVN) represent a significant problem after kidney transplantation. Both are associated with intensified immunosuppression, but other risk factors and the impact of a screening program on outcome are incompletely understood.. Here, we report on the short- and long-term outcome of a cohort of patients, who were transplanted in 2006/2007 and included in a newly introduced systematic 3-monthly screening for BK viremia at the University Hospital Zurich. In patients testing positive for BK viremia, screening frequency was intensified and immunosuppression reduced. Patients with suspected PVN underwent transplant biopsy.. Among 152 included patients, 49 (32%) tested positive for BK viremia, but only 8 developed biopsy-proven PVN. BK viremia had a significant impact on estimated glomerular filtration rate and proteinuria in the first 2 years. Acute rejection episodes and the number of human leukocyte antigen (HLA) mismatches were the strongest independent predictors of BK viremia in a multiple logistic model. In contrast, no particular immunosuppressive agent or regimen was associated with enhanced risk.. Taken together, systematic BK viremia screening led to detection of a high percentage of viremic patients. With adjustment of immunosuppression, an excellent outcome was achieved. The independent association of HLA mismatches with BK viremia suggests impaired polyomavirus immunosurveillance in highly mismatched allografts.

Topics: Adult; Aged; Allografts; Antibodies, Monoclonal; Azathioprine; Basiliximab; BK Virus; Cohort Studies; Cyclosporine; Female; Glomerular Filtration Rate; Graft Rejection; Histocompatibility; HLA Antigens; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Logistic Models; Male; Middle Aged; Multivariate Analysis; Mycophenolic Acid; Polyomavirus Infections; Proteinuria; Pyrroles; Quinazolines; Recombinant Fusion Proteins; Tacrolimus; Tumor Virus Infections; Viremia

To retrospectively investigate clinico-pathological features and outcomes of patients with renal involvement in propylthiouracil (PTU)-associated antineutrophil cytoplasmic autoantibody (ANCA) vasculitis (PTU-AAV).. Clinico-pathological features and outcomes of 12 patients (female 11, average age 32.4 ± 13.8 years) who developed AAV after treatment with PTU were collected and analyzed. ANCA was detected by both immunofluorescence (IF) and enzyme linked immunosorbent assay (ELISA). All patients had renal biopsy.. Twelve patients received PTU for 2-264 months (median 42 months) when PTUAAV was diagnosed. All patients had positive serum P-ANCA, 11 of them were MPO-ANCA, 1 was MPO and PR3-ANCA double positive. All patients presented with hematuria and proteinuria, 5 of them had gross hematuria, urine protein was 1.9 ± 1.6 g/24 h, 7 of 12 (58.3%) patients had renal dysfunction, among them 3 needed initial renal replacement therapy. Renal biopsy showed pauci-immune segmental necrotizing crescentic glomerulonephritis in ten patients, segmental necrotizing glomerulonephritis superimposed on membranous nephropathy in two patients. All patients withdrew PTU and received steroid and immunosuppressive therapy. After a median follow-up of 42 months (range 21-86), 3 patients developed to ESRD, 7 patients entered complete renal remission. Serum ANCA turned negative only in 2 patients, 10 patients had persistent positive serum ANCA. Three patients relapsed with the elevation of serum ANCA level.. Renal damage of PTU-AAV could be pauci-immune necrotizing crescentic glomerulonephritis, and necrotizing glomerulonephritis coexisted with membranous nephropathy. Most patients had persistent positive serum ANCA and had a risk of relapse and progression to ESRD even after PTU withdrawal and immunosuppressive therapy.

Topics: Adolescent; Adult; Anti-Inflammatory Agents; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antithyroid Agents; Child; Cyclophosphamide; Disease Progression; Hematuria; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Glomerulus; Kidney Tubules; Male; Middle Aged; Mycophenolic Acid; Prednisone; Propylthiouracil; Proteinuria; Recurrence; Remission Induction; Renal Replacement Therapy; Retrospective Studies; Thyroid Diseases; Young Adult

Rare cases of association between lupus nephritis (LN) and minimal changes nephrotic syndrome (MCNS) were described. Some authors suggest that this association, taking into account the low prevalence of both diseases, may not be a simple coincidence. Several pathophysiological hypotheses have been proposed to explain this association, including a potential central role of T lymphocytes.. We describe the case of a 21 years-old female patient who initially presented with isolated nephrotic range proteinuria. She had no evidence of systemic involvement and Immunological tests were negative, including anti-neutrophil antibodies (ANA) and anti-double-stranded DNA antibodies (Anti-dsDNA). Renal biopsy showed normal glomeruli under light microscopy and no significant deposits were found in immunofluorescence studies. She was diagnosed to have MCNS and responded to a short course of steroids. She remained in remission for three years, after which she presented again with nephrotic-range proteinuria accompanied by clinical signs of systemic involvement. During her second presentation, she fulfilled the diagnostic criteria of systemic lupus erythematosus (SLE) and another kidney biopsy showed class-V lupus nephritis. She was treated with pulse steroids followed by oral prednisolone and mycophenolate mofetil, with good clinical response.. This case indicates that relapses of MCNS should be carefully investigated in the right setting to avoid missing a systemic disease such as SLE.

Topics: Antibodies, Antinuclear; Female; Humans; Lupus Erythematosus, Systemic; Lupus Nephritis; Mycophenolic Acid; Nephrosis, Lipoid; Prednisolone; Proteinuria; Young Adult

The ability to selectively inactivate immune cells with immunosuppressants is a much sought-after modality for the treatment of systemic lupus erythematosus and autoimmunity in general. Here, we designed and tested a novel nanogel drug delivery vehicle for the immunosuppressant mycophenolic acid (MPA). Treatment with MPA-loaded nanogels increased the median survival time (MST) of lupus-prone NZB/W F1 mice by 3 months with prophylactic use (MST was 50 weeks versus 38 weeks without treatment), and by 2 months when administered after the development of severe renal damage (MST after proteinuria onset was 12.5 weeks versus 4 weeks without treatment). Equivalent and greater doses of MPA administered in buffer were not efficacious. Nanogels had enhanced biodistribution to organs and association with immune cells. CD4-targeted nanogels yielded similar therapeutic results compared with nontargeted formulations, with protection from glomerulonephritis and decreases in IFN-γ-positive CD4 T cells. DCs that internalized nanogels helped mediate immunosuppression, as they had reduced production of inflammatory cytokines such as IFN-γ and IL-12. Our results demonstrate efficacy of nanogel-based lupus therapy and implicate a mechanism by which immunosuppression is enhanced, in part, by the targeting of antigen-presenting cells.

Topics: Animals; Blood Urea Nitrogen; Cells, Cultured; Cyclodextrins; Dendritic Cells; Female; Kidney; Lactic Acid; Liposomes; Lupus Erythematosus, Systemic; Mice; Mice, Inbred BALB C; Mycophenolic Acid; Nanocapsules; Nanoconjugates; Polyesters; Polyethylene Glycols; Polymers; Proteinuria; T-Lymphocytes; Tissue Distribution

Lupus nephritis (LN) is usually associated with widespread effacement of the podocytes' foot processes leading to proteinuria. Induction of urokinase receptor (uPAR) signaling in podocytes leads to foot process effacement and urinary protein loss via promoting podocytes' motility and kidney permeability in the glomerulus. Very little is known about uPAR signaling in LN. Mycophenolate mofetil (MMF), an immunosuppressive agent, efficiently modulates the development of LN in humans and mice, but there are no data concerning the direct uPAR involvement on podocytes in LN. The MMF efficiency and uPAR involvement signaling in NZB×NZW F1 lupus-prone mice were examined by proteinuria, renal function and pathology, immune complex deposits, and uPAR expression of podocytes by immunofluorescence staining and quantitative RT-PCR. After MMF treatment, the proteinuria (p < 0.01), BUN level (p < 0.05) and immunodeposition in glomeruli (p < 0.001) were significantly improved. Most important, the renal uPAR mRNA levels (p < 0.001) and uPAR protein level of podocytes (p < 0.001) were significantly reduced. The beneficial effect of MMF on LN could be attributed, at least in part, to the inhibition of uPAR expression in podocytes. These findings demonstrated uPAR could have potential as a predictive index for response to LN therapeutics.

Topics: Animals; Blood Urea Nitrogen; Disease Models, Animal; Female; Fluorescent Antibody Technique; Humans; Immunosuppressive Agents; Lupus Nephritis; Mice; Mice, Inbred NZB; Mycophenolic Acid; Podocytes; Proteinuria; Receptors, Urokinase Plasminogen Activator; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction

To investigate the efficacy of different doses of the soluble form of the receptor for advanced glycation end products (sRAGE) (conjugated to the Fc portion of immunoglobulin) in the treatment of nephritis in lupus-prone mice, in comparison with the efficacy of combination therapy with mycophenolate mofetil plus prednisolone.. Twenty-eight female (NZB/NZW)F1 mice were divided into 5 groups (untreated, sRAGE [dose groups of 0.5, 1, or 2 μg], or mycophenolate mofetil plus prednisolone). Proteinuria and histologic damage were evaluated. Immune complex deposition and the nuclear translocation of NF-κB in the kidney tissue were assessed by immunofluorescence staining. Serum concentrations of anti-double-stranded DNA (anti-dsDNA) and IgG subclasses were also measured. The population of T cells was evaluated using a fluorescence-activated cell sorter, and expression of intracellular adhesion molecule 1 and vascular cell adhesion molecule 1 in the kidney tissue was assessed by immunohistochemical staining.. In comparison with untreated mice, mice treated with 1 or 2 μg sRAGE showed significantly reduced proteinuria and attenuated histologic renal damage, with efficacy comparable to that of combination therapy. Treatment with 2 μg sRAGE significantly reduced immune complex deposition and decreased the serum concentrations of anti-dsDNA, IgG2a, IgG2b, and IgG3. In addition, sRAGE interrupted the nuclear translocation of NF-κB in the kidney, resulting in reduction in the expression of downstream genes of NF-κB in vivo and in vitro. Furthermore, sRAGE effectively modified T cell populations.. Treatment with sRAGE significantly improved nephritis in lupus-prone mice, with efficacy comparable to that of standard induction treatment for lupus nephritis. These data suggest that sRAGE has antiinflammatory effects on the pathophysiology of lupus nephritis and could serve as a potent new therapy for this disease.

Topics: Animals; Anti-Inflammatory Agents; Antigen-Antibody Complex; Disease Models, Animal; Drug Therapy, Combination; Female; Kidney; Lupus Nephritis; Mice; Mice, Inbred NZB; Mycophenolic Acid; NF-kappa B; Prednisolone; Proteinuria; Receptor for Advanced Glycation End Products; Receptors, Immunologic; Treatment Outcome

Treatment of patients with resistant/relapsed adult nephrotic syndrome (RNS) caused by glomerulopathies has no consensus therapy.. This is a retrospective analysis (RA), performed on 55 patients with RNS treated during one year with enteric coated sodium mycophenolate (EC-MPS) and reduced corticosteroids doses.. Inclusion criteria for this RA were: patients aged ≥ 18 years old, diagnosed with RNS with histologically proven glomerulopathy who had received standard therapy with enalapril and/or losartan and 10 mg per day or 20 mg of prednisone every other day. NS was defined with the following criteria: proteinuria > 3.5 g/day, serum albumin ≤ 3 g/dl, hypercholesterolemia and edema. Treatment consisted of oral EC-MPS in 360 mg tablets, 720 mg bid, together with prednisone 10 mg daily or 20 mg every other day. Effectiveness was assessed as the rate of response in the cohort: complete, partial or absent. Complete response patients: 24 hours proteinuria < 300 mg/day, partial response patients: proteinuria > 300 mg/day and < than 3 g/day, all the rest were considered as non responders.. response was achieved in 40/55 (73%) of patients, 24 (44%) with complete response and 16 (29%) with partial response. No EC-MPS discontinuation has been observed due to adverse events, except for one case of transient interruption of medication for 2 weeks.. EC-MPS as single therapy with minimal doses of corticosteroids as in this RA could be an effective alternative in the treatment of patients with RNS.

Topics: Adolescent; Adult; Aged; Cohort Studies; Drug Resistance; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Glucocorticoids; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Nephrotic Syndrome; Prednisone; Proteinuria; Remission Induction; Retrospective Studies; Tablets, Enteric-Coated; Treatment Outcome

A 26-year-old man diagnosed with nephrotic syndrome was administered steroid monotherapy. Urinary protein excretion was 2-3 g/day despite the therapy. Percutaneous renal biopsy revealed Type I idiopathic membranoproliferative glomerulonephritis (IMPGN). Although intravenous steroid therapy at the dose of 1,000 mg/day for 3 days was administered, proteinuria persisted at the level of 1 g/day. Renal dysfunction (cystatin C, 1.33 mg/L) was evident. Strong inflammation was suggested by occult blood (3+) and urinary (red blood cells: 30-50/high power field) sediment. We considered steroid monotherapy to be ineffective, and initiated combina-tion therapy with mycophenolate mofetil (MMF) and steroids. Consequently, urinary protein excretion moderately decreased to 0.34 g/day without adverse events or worsening of the renal function. The steroid quantity could be reduced without relapse. Subsequently, we were able to reduce the dose of MMF gradually, then terminated the medication. IMPGN is a rare disease with a poor renal prognosis. Recently, MMF therapies for IMPGN have been attempted, but there are few cases in Japan. Our case suggests that combination therapy with MMF and steroids is effective and safe for treating IMPGN.

Topics: Adult; Biopsy, Needle; Drug Therapy, Combination; Glomerulonephritis, Membranoproliferative; Humans; Kidney; Male; Mycophenolic Acid; Nephrotic Syndrome; Proteinuria; Steroids; Treatment Outcome

Complement 3 glomerulopathy (C3GN) is a newly proposed subcategory of glomerular disease with features including membranoproliferative glomerulonephritis (MPGN), C3-dominant immunofluorescent staining without appreciable immunoglobulin deposition, and electron-dense deposits. Aberrations of alternative complement pathway (AP) have been found in many C3GN patients.. A 13-year-old boy presented with edema in association with an upper respiratory infection. Studies demonstrated nephrotic syndrome with hematuria and markedly low C3 and C4. Initial renal biopsy showed MPGN with strong C3 and immunoglobulin deposition. The patient partially responded to immunosuppression. Follow-up biopsies at 10 months and 3 years demonstrated MPGN with strong C3, with little to no immunoglobulin deposition. Based on this and elevated SC5b-9, treatment was changed to eculizumab with further decrease in proteinuria.. Serial biopsies illustrated marked variability in immunoglobulin deposition in MPGN with persistently strong C3 deposition. Whether this evolution was related to the course of disease or to therapeutic intervention, the pathologic progression documented in this series of biopsies challenges the newly proposed subcategories of MPGN.

Topics: Adolescent; Anti-Inflammatory Agents; Biopsy; Complement C3; Creatinine; Glomerulonephritis, Membranoproliferative; Humans; Immunoglobulins; Immunohistochemistry; Immunosuppressive Agents; Kidney; Kidney Function Tests; Male; Methylprednisolone; Microscopy, Electron; Mycophenolic Acid; Prednisone; Proteinuria; Staphylococcal Infections

A 20-year-old woman presented with common cold symptoms was found to have a left-sided facial droop. On examination, peripheral facial nerve palsy was confirmed. Subsequent testing showed nephrotic range proteinuria and positive serologies including antinuclear antibody and anti-smith antibody. Kidney biopsy showed stage III lupus nephritis. Treatment with pulse steroids along with mycophenolate mofetil for her lupus nephritis resulted in concomitant improvement of her facial palsy.

Topics: Adrenal Cortex Hormones; Facial Paralysis; Female; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Lupus Nephritis; Mycophenolic Acid; Proteinuria; Young Adult

We report the case of a 19-year-old woman with progressive proliferative lupus nephritis (LN) class III after induction and maintenance therapy with mycophenolate mofetil (MMF). Despite a satisfying clinical improvement proteinuria progressed under this medication. We treated the patient with additional belimumab after discussing other options. Following treatment with belimumab, proteinuria rapidly improved to almost normal levels and clinical remission lasted. Belimumab might hold promise for this indication.

Topics: Antibodies, Monoclonal, Humanized; Disease Progression; Female; Humans; Immunosuppressive Agents; Lupus Nephritis; Mycophenolic Acid; Proteinuria; Remission Induction; Treatment Outcome; Young Adult

X-linked agammaglobulinaemia (XLA) is the most common inherited humoural immunodeficiency disorder. Mutations in the gene coding for Bruton's tyrosine kinase (BTK) have been identified as the cause of XLA. Most affected patients exhibit a marked reduction of serum immunoglobulins, mature B cells, and an increased susceptibility to recurrent bacterial infections. However, the diagnosis of XLA can be a challenge in certain patients who have near-normal levels of serum immunoglobulin. Furthermore, reports on XLA with renal involvement are scant.. We report an atypical XLA patient who presented with selective immunoglobulin M (IgM) immunodeficiency and nephropathy. He was diagnosed with selective IgM immunodeficiency, based on his normal serum immunoglobulin G (IgG) and immunoglobulin A (IgA) levels but undetectable serum IgM level. Intravenous immunoglobulin was initiated due to increased infections and persistent proteinuria but no improvement in proteinuria was found. A lupus-like nephritis was detected in his kidney biopsy and the proteinuria subsided after receiving a mycophenolate mofetil regimen. Although he had a history of recurrent bacterial infections since childhood, XLA was not diagnosed until B-lymphocyte surface antigen studies and a genetic analysis were conducted.. We suggest that B-lymphocyte surface antigen studies and a BTK mutation analysis should be performed in familial patients with selective IgM deficiency to rule out atypical XLA.

Topics: Agammaglobulinemia; Antigens, Differentiation, B-Lymphocyte; Child; Genetic Diseases, X-Linked; Humans; Immunoglobulin M; Male; Mycophenolic Acid; Nephritis; Proteinuria

Topics: Antihypertensive Agents; Cyclophosphamide; Cyclosporine; Drug Substitution; Drug Therapy, Combination; Fatigue; Glomerulosclerosis, Focal Segmental; Gynecomastia; Humans; Hypertension; Male; Mastodynia; Middle Aged; Muscle Weakness; Mycophenolic Acid; Prednisone; Proteinuria; Tacrolimus

Tremendous breakthrough in solid organ transplantation was made with the introduction of calcineurin inhibitors (CNI). At the same time, they are potentially nephrotoxic drugs with influence on onset and progression of renal graft failure. The aim of this study was to evaluate the outcome of a conversion from CNI-based immunosuppressive protocol to sirolimus (SRL) in recipients with graft in chronic kidney disease (CKD) grade III and proteinuria below 500 mg/day.. In the period 2003-2011 24 patients (6 famale and 18 male), mean age 41 +/- 12.2 years, on triple immunosuppressive therapy: steroids, antiproliferative drug [mycophenolate mofetil (MMF) or azathiopirine (AZA)] and CNI were switched from CNI to SRL and followe-up for 76 +/- 13 months. Nine patients (the group I) had early postransplant conversion after 4 +/- 3 months and 15 patients (the group II) late conversion after 46 +/- 29 months. During the regular outpatient controls we followed graft function through the serum creatinine and glomerular filtration rate (GFR), proteinuria, lipidemia and side effects.. Thirty days after conversion, in all the patients GFR, proteinuria and lipidemia were insignificantly increased. In the first two post-conversion months all the patients had at least one urinary or respiratory infection, and 10 patients reactivated cytomegalovirus (CMV) infection or disease, and they were successfully treated with standard therapy. After 21 +/- 11 months 15 patients from both groups discontinued SRL therapy due to reconversion to CNI (10 patients) and double immunosuppressive therapy (3 patients), return to hemodialysis (1 patient) and death (1 patient). Nine patients were still on SRL therapy. By the end of the follow-up they significantly improved GFR (from 53.2 +/- 12.7 to 69 +/- 15 mL/min), while the increase in proteinuria (from 265 +/- 239 to 530.6 +/- 416.7 mg/day) and lipidemia (cholesterol from 4.71 +/- 0.98 to 5.61 +/- 1.6 mmol/L and triglycerides from 2.04 +/- 1.18 to 2.1 +/- 0.72 mmol/L) were not significant. They were stable during the whole follow-up period. Ten patients were reconverted from SRL to CNI due to the abrupt increase of proteinuria (from 298 +/- 232 to 1639 +/- 1641/mg day in 7 patients), rapid growth of multiple ovarian cysts (2 patients) and operative treatment of persisted hematoma (1 patient). Thirty days after reconversion they were stable with an insignificant decrease in GFR (from 56.10 +/- 28.09 to 47 +/- 21 mL/min) and significantly improved proteinuria (from 1639 +/- 1641 to 529 +/- 688 mg/day). By the end of the follow-up these patients showed nonsignificant increase in the serum creatinine (from 172 +/- 88 to 202 +/- 91 mmol/L), decrease in GFR (from 56.10 +/- 28.09 to 47 +/- 21 mL/day) and increased proteinuria (from 528.9 +/- 688 to 850 +/- 1083 mg/min).. In this small descriptive study, conversion from CNI to SRL was followed by an increased incidence of infections and consecutive 25-50% dose reduction in the second antiproliferative agent (AZA, MMF), with a possible influence on the development of glomerulopathy in some patients, which was the major reason for discontinuation of SRL therapy in the 7 (29%) patients. Nine (37.5%) of the patients experienced the greatest benefit of CIN to SRL conversion without serious post-conversion complications.

Topics: Adult; Azathioprine; Biomarkers; Calcineurin Inhibitors; Creatinine; Cytomegalovirus Infections; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Proteinuria; Renal Insufficiency, Chronic; Sirolimus; Time Factors; Treatment Outcome

Nephrotic syndrome (NS) is a recognized complication of immune tolerance induction (ITI) therapy, a treatment strategy used to treat inhibitors in patients with hemophilia B receiving factor IX concentrate.. We present a 4-year-old boy with hemophilia B and an inhibitor who underwent ITI, and developed NS 19 months into this therapy. A percutaneous renal biopsy was safely performed with factor IX (FIX) concentrate administration both preceding and following the procedure. The patient's inhibitor level had increased to 1.4-1.6 Bethesda Units just prior to the onset of proteinuria. Histology confirmed segmental membranous nephropathy (MGN). The patient was continued on FIX concentrate as ITI and also received 4 weekly doses of rituximab and ongoing immunosuppression with mycophenolate mofetil. This resulted in the complete resolution of his inhibitor and his NS. He continues with a modified ITI regimen and remains inhibitor-free without proteinuria >12 months post-biopsy.. Hemophilia B patients undergoing ITI should be regularly screened for NS. At first detection of proteinuria, with proper precautions, a percutaneous kidney biopsy can be performed safely in patients with low levels of inhibitor. Our patient had segmental MGN with complete remission of NS.

Topics: Antibodies; Antibodies, Monoclonal, Murine-Derived; Biopsy; Child, Preschool; Coagulants; Factor IX; Glomerulonephritis, Membranous; Hemophilia B; Humans; Immune Tolerance; Immunosuppressive Agents; Male; Mycophenolic Acid; Nephrotic Syndrome; Proteinuria; Rituximab; Time Factors; Treatment Outcome

Topics: Acute Kidney Injury; Adult; Blood Component Transfusion; Bone Marrow; Cell Lineage; Combined Modality Therapy; Darbepoetin alfa; Erythropoietin; Filgrastim; Granulocyte Colony-Stimulating Factor; Hematuria; Humans; Lupus Erythematosus, Systemic; Lupus Nephritis; Lymphohistiocytosis, Hemophagocytic; Male; Mycophenolic Acid; Myelodysplastic Syndromes; Pancytopenia; Pericarditis; Prednisone; Proteinuria; Recombinant Proteins

Henoch-Schönlein purpura (HSP) can progress to Henoch-Schönlein purpura nephritis (HSPN), and the most effective management remains unclear. Our aim was to evaluate the efficacy of mycophenolate mofetil (MMF) for treating pediatric patients with HSPN and nephrotic-range proteinuria.. Twelve children, seven boys and five girls, mean age 8.33 (range 6-12) years at the time of HSPN diagnosis with nephrotic-range proteinuria, were treated with MMF. All patients failed steroid treatment, and mean proteinuria at the time of MMF initiation was 5.6 g/d. MMF dosage ranged from 20 to 25 mg/kg per day. Patients also received an angiotensin-converting enzyme inhibitor (cliazapril) at MMF initiation. Mean follow-up was 3.9 (range 2.3-5.5) years.. All patients responded to MMF at a mean of 2.5 (range 1-4 months). Among the 12 patients, MMF was administered for 10 months in five, 12 months in six, and 15 months in one. At last follow-up, all patients had negative proteinuria and normal renal function, and no relapses were noted. No serious adverse effects of MMF were noted in any patient.. MMF is useful for treating pediatric patients with HSPN and nephrotic-range proteinuria.

Topics: Angiotensin-Converting Enzyme Inhibitors; Biopsy; Child; Cyclophosphamide; Drug Resistance; Female; Follow-Up Studies; Humans; IgA Vasculitis; Immunosuppressive Agents; Kidney; Kidney Function Tests; Leukocyte Count; Male; Mycophenolic Acid; Nephritis; Proteinuria; Retrospective Studies; Steroids

Chronic renal transplant dysfunction is histopathologically characterized by interstitial fibrosis and tubular atrophy. This study investigated the relative contribution of baseline donor, recipient, and transplant characteristics to interstitial fibrosis and tubular atrophy score at month 12 after renal transplantation.. This retrospective study includes all 109 consecutive recipients with adequate implantation and month 12 biopsies transplanted between April of 2003 and February of 2007. Immunosuppression regimen was tacrolimus and steroids (10 days) plus either sirolimus or mycophenolate mofetil.. Average interstitial fibrosis and tubular atrophy score increased from 0.70 to 1.65 (P<0.001). In an adjusted multiple linear regression analysis, interstitial fibrosis and tubular atrophy score at month 12 was significantly related to donor type (donors after cardiac death versus living donor had interstitial fibrosis and tubular atrophy score+0.41, 95% confidence interval=0.05-0.76, P=0.02), baseline interstitial fibrosis and tubular atrophy, and immunosuppression regimen. Because of interaction between the latter two variables (P=0.002), results are given separately: recipients with a baseline interstitial fibrosis and tubular atrophy score of zero had a 0.60 higher score at month 12 (95% confidence interval=0.09-1.10, P=0.02) when mycophenolate mofetil-treated, whereas recipients with a baseline interstitial fibrosis and tubular atrophy score more than zero had a 0.38 higher score at month 12 (95% confidence interval=0.01-0.74, P=0.04) when sirolimus-treated. A higher score at month 12 correlated with a lower estimated GFR (ρ=-0.45, P<0.001).. These findings suggest that histologic assessment of a preimplantation biopsy may guide choice of immunosuppresion to maximize transplant survival and its interaction with type of immunosuppression.

Topics: Adult; Aged; Atrophy; Biopsy; Drug Therapy, Combination; Female; Fibrosis; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Kidney Tubules; Linear Models; Male; Middle Aged; Multivariate Analysis; Mycophenolic Acid; Netherlands; Proteinuria; Retrospective Studies; Risk Assessment; Risk Factors; Sirolimus; Steroids; Tacrolimus; Time Factors; Treatment Outcome

To describe the clinical characteristics, histopathologic features, and outcomes of patients in whom vasculitis developed in association with use of tumor necrosis factor-α (TNF-α) inhibitors.. This is a retrospective review of patients evaluated at Mayo Clinic, Rochester, Minnesota, from January 1, 1998, through March 31, 2011, with a diagnosis of vasculitis induced by anti-TNF-α therapy.. Of 8 patients with vasculitis associated with anti-TNF-α therapy (mean age, 48.5 years), 6 (75%) were female. Four (50%) had rheumatoid arthritis, 1 (13%) had Crohn disease, and 3 (38%) had ulcerative colitis. Five (63%) were treated with infliximab, 2 (25%) with etanercept, and 1 (13%) with adalimumab. The mean duration of treatment before development of vasculitis was 34.5 months. The skin was the predominant organ affected (5 patients [63%]), with the most common cutaneous lesion being palpable purpura (4 of 5 [80%]). Two organs involved in systemic vasculitis were the peripheral nervous system (4 patients [50%]) and kidney (1 patient [13%]). All cases of vasculitis were histopathologically confirmed. Seven of 8 patients improved with discontinuation of therapy (mean time to resolution, 6.9 months) and adjuvant treatment (all 8 received prednisone; another agent was also used in 7); rechallenge with anti-TNF-α therapy was not attempted in any patient. At last follow-up, no patients had experienced a recurrence of vasculitis after therapy discontinuation.. Cutaneous small-vessel vasculitis was the most common finding, but systemic vasculitis, including peripheral nerve and renal vasculitis, was also frequently observed.

Topics: Adalimumab; Adult; Aged; Anti-Inflammatory Agents; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Arthritis, Rheumatoid; Azathioprine; Colitis, Ulcerative; Crohn Disease; Cyclophosphamide; Etanercept; Female; Glucocorticoids; Hematuria; Humans; Immunoglobulin G; Immunologic Factors; Infliximab; Male; Methotrexate; Middle Aged; Mycophenolic Acid; Polyneuropathies; Prednisone; Proteinuria; Receptors, Tumor Necrosis Factor; Retrospective Studies; Rituximab; Tumor Necrosis Factor-alpha; Vasculitis; Young Adult

Thalidomide has various effects, such as immune modulation, anti-angiogenicity, anti-inflammation and anti-proliferation. Moreover, thalidomide modulates the activity of NF-κB, which can up-regulate the expression of downstream genes involved in the pathophysiology of LN. Here we investigated the efficacy of thalidomide monotherapy or thalidomide plus prednisolone (PL) on nephritis in NZB/WF1 mice at different doses and compared both with a combination therapy of MMF plus PL.. Forty-three female NZB/WF1 mice were divided into eight groups (untreated; 1.7, 5 or 10 mg/kg of thalidomide alone; 1.7, 5 or 10 mg/kg of thalidomide plus 1.5 mg/kg of PL and 33.3 mg/kg of MMF plus PL). Proteinuria and histological damage were evaluated. Immune complex deposition and nuclear translocation of NF-κB in kidney tissues were assessed by immunofluorescence staining. Serum concentrations of anti-dsDNA and IgG subclasses were also measured.. In comparison with untreated mice, mice treated with 10 mg/kg of thalidomide monotherapy showed a significant decrease in proteinuria and significantly lower glomerular and tubular damage scores, comparable to 5 or 10 mg/kg of thalidomide plus PL or MMF plus PL. Also, treatment with 10 mg/kg of thalidomide significantly decreased immune complex accumulation, reduced the serum concentration of anti-dsDNA, IgG2a and IgG2b and inhibited nuclear translocation of NF-κB in kidney tissues, comparable to standard therapy for LN.. These data suggest that thalidomide might play an anti-inflammatory role in the pathophysiology of LN, and it could serve as a complementary therapy to standard induction regimens for refractory LN.

Topics: Animals; Anti-Inflammatory Agents; Antigen-Antibody Complex; DNA; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Glomerulonephritis; Immunoglobulin G; Immunosuppressive Agents; Lupus Nephritis; Mice; Mice, Inbred NZB; Mycophenolic Acid; Prednisolone; Proteinuria; Survival Rate; Thalidomide

Henoch-Schönlein purpura (HSP) is a form of systemic vasculitis that can progress to Henoch-Schönlein purpura nephritis (HSPN), and the most effective treatment remains controversial. Our aim was to compare the effects of oral mycophenolate mofetil (MMF) with low-dose prednisone and the full-dose corticosteroids (CS; prednisone) for the induction therapy of HSPN with large proteinuria.. Fifty-three patients with biopsy-proved HSPN with large proteinuria (>2.0 g/24 h) were divided into two groups: the MMF group (n = 27) who received oral MMF 1.0 g/day (1.5 g/day for patients with a body weight >70 kg) combined with low-dose prednisone (0.4-0.5 mg/kg/day), and the CS group (n = 26) who received the full-dose prednisone (0.8-1.0 mg/kg/day). We compared the effects of inducing remission at 6-month follow-up and the overall remission rate at the end of the follow-up between the two groups.. At 6 months, the estimated glomerular filtration rate level remained stable, while the urine protein decreased significantly in both groups, and the remission rate was 76.9% in the CS group and 55.5% in the MMF group (p = 0.101). With a median follow-up of 28.8 months in the CS group and 28.2 months in the MMF group, the overall remission rate was 80.8% in the CS group and 77.8% in the MMF group (p = 0.788). The MMF group had less side effects than the CS group (48.1 vs. 76.9%, p = 0.031). The relapse was 4/21 (19.0%) in the CS group and 0/21 in the MMF group (p = 0.115).. MMF is useful for inducing remission and maintaining remission in Chinese HSPN, and may be used as a steroid-sparing agent in the treatment of HSPN.

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Aged; Biopsy; China; Drug Therapy, Combination; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; IgA Vasculitis; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Nephritis; Proteinuria; Recurrence; Remission Induction; Retrospective Studies

Nephrotoxicity is a major complication with immunosuppression regimens used in transplantation. Calcineurin inhibitor-sparing or reduction regimens using sirolimus (SRL) have shown variable success in kidney transplantation. There is limited data on the role of SRL on native kidney function in pancreas transplantation.. All patients undergoing pancreas transplantation from 2003 to 2010 were enrolled in this study (n=65). Patient demographic characteristics were identified and divided into two groups: those receiving tacrolimus (Tac) in combination with mycophenolate mofetil (MMF) and those maintained on a regimen of Tac and SRL with or without MMF. The slopes for estimated glomerular filtration rate (eGFR), serum creatinine level (sCr), and proteinuria changes over time were assessed between groups. Urine protein and creatinine ratio (uPr/uCr) was used to assess proteinuria.. There was no difference in baseline demographic characteristics. Patients were followed for a median of 3 years. Baseline sCr and eGFR were similar between groups. Differences in uPr/uCr and rate of change in sCr and eGFR were not significant between the groups overall or for any specific time. There was worsening of sCr, eGFR, and uPr/uCr within the groups over the period of study. There were no significant differences when groups were split by age or gender or when the SRL group was split further based on MMF inclusion.. Our study findings suggest that using a Tac-SRL regimen in patients with pancreas alone transplantation is a safe approach and may not lead to worsening proteinuria and kidney function when compared with regimens using Tac with MMF.

Topics: Adult; Age Factors; Biopsy; Creatinine; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Kidney; Male; Middle Aged; Mycophenolic Acid; Pancreas Transplantation; Proteinuria; Retrospective Studies; Sex Factors; Sirolimus; Tacrolimus

We report hypokalaemic quadriparesis presenting in a 43-year-old woman. Evaluation revealed hypokalaemic quadriparesis secondary to underlying distal renal tubular acidosis, also known as type 1 RTA. Four years after the diagnosis of RTA, the patient developed joint pain, and investigation revealed systemic lupus erythematosus with lupus nephritis. RTA is one of the very rare presentations of systemic lupus erythematosus. Thus, tubular dysfunction should be carefully assessed in patients with systemic lupus erythematosus. Similarly, patients with RTA should be evaluated for underlying lupus. Our patient was successfully treated with mycophenolate mofetil and steroids.

Topics: Acidosis, Renal Tubular; Acute Disease; Adult; Blood Sedimentation; Female; Humans; Hypokalemia; Lupus Erythematosus, Systemic; Muscles; Mycophenolic Acid; Paralysis; Proteinuria; Steroids; Treatment Outcome

We report the case of a 38-year-old male with autosomal-dominant polycystic kidney disease (ADPKD) and concomitant nephrotic syndrome secondary to membranous nephropathy (MN). A 3-month course of prednisone 60 mg daily and losartan 100 mg daily resulted in resistance. Treatment with chlorambucil 0.2 mg/kg daily, low-dose prednisone, plus an angiotensin-converting enzyme inhibitor (ACEI) and an angiotensin II receptor blocker (ARB) for 6 weeks resulted in partial remission of his nephrotic syndrome for a duration of 10 months. After relapse of the nephrotic syndrome, a 13-month course of mycophenolate mofetil (MFM) 2 g daily and low-dose prednisone produced complete remission for 44 months. After a new relapse, a second 24-month course of MFM and low-dose prednisone produced partial to complete remission of proteinuria with preservation of renal function. Thirty-six months after MFM withdrawal, complete remission of nephrotic-range proteinuria was maintained and renal function was preserved. This case supports the idea that renal biopsy is needed for ADPKD patients with nephrotic-range proteinuria in order to exclude coexisting glomerular disease and for appropriate treatment/prevention of renal function deterioration. To the best of our knowledge, this is the first reported case of nephrotic syndrome due to MN in a patient with ADPKD treated with MFM, with remission of proteinuria and preservation of renal function after more than 10 years. Findings in this patient also suggest that MFM might reduce cystic cell proliferation and fibrosis, preventing progressive renal scarring with preservation of renal function.

Topics: Adult; Biopsy; Glomerulonephritis, Membranous; Humans; Kidney; Male; Mycophenolic Acid; Nephrotic Syndrome; Polycystic Kidney, Autosomal Dominant; Proteinuria

Refractory nephrotic syndrome (NS) is problematic because the optimal therapy for this disease is unclear and because persistent NS progresses eventually to end-stage renal disease. We report our experience using a combination of corticosteroid, cyclosporine A (CsA), and mycophenolate mofetil (MMF) to treat 10 refractory NS patients.. Ten refractory NS patients, who showed resistance to corticosteroid and CsA, were treated with triple immunosuppressive therapy. Cyclophosphamide and MMF had been used previously in 6 patients, but had failed to induce remission.. Triple immunosuppressive therapy was discontinued after 4 months in 1 patient because of progressive azotemia. Partial remission was achieved in 9 of the 10 patients after 10 months, and remission was maintained during the treatment (urine protein to creatinine ratio, mg/mg, baseline vs. 12th month; 5.7 ± 1.8 vs. 1.4 ± 0.7). Renal function was preserved in these 9 patients (estimated GFR, ml/min/1.73 m2, baseline vs. 12th month; 71.4 ± 29.1 vs. 68.9 ± 31.5). Of the 7 patients who discontinued triple immunosuppressive therapy, remission and renal function were maintained in 4 patients.. Triple immunosuppressive therapy significantly reduced proteinuria and preserved renal function in refractory NS patients, indicating a promising role of this therapy for refractory NS.

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Aged; Cyclosporine; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Nephrotic Syndrome; Proteinuria; Remission Induction; Statistics, Nonparametric; Treatment Outcome

Topics: Aged; Biopsy, Needle; Female; Fluorescent Antibody Technique; Follow-Up Studies; Glomerulonephritis, IGA; Graft Rejection; Humans; Immunohistochemistry; Immunosuppressive Agents; Kidney Transplantation; Living Donors; Mycophenolic Acid; Proteinuria; Recurrence; Risk Assessment; Treatment Outcome

Since the efficacy of mycophenolate mofetil (MMF) to treat immunoglobulin A (IgA) nephropathy is controversial, we extended our original study by following 40 Chinese patients with established IgA nephropathy for 6 years. All patients were maintained on their angiotensin blockade medication and half were randomized to receive MMF for 6 months. After 6 years, 11 patients required dialysis (2 from the MMF and 9 from the control group). Significantly, only 3 treated (as compared to 10 control) patients reached the composite end point of serum creatinine doubling or end-stage renal disease. Linear regression showed the annualized decline in the estimated glomerular filtration rate was significantly less in the MMF-treated group. Urinary protein excretion and the albumin-to-creatinine ratio were lower with MMF treatment during the first 24 months, beyond which there was no difference between groups. Multivariable Cox regression analysis showed that the baseline estimated glomerular filtration rate and proteinuria, and change in the urine albumin-to-creatinine ratio at 1 year to be important predictors of progression to end-stage renal disease. We found that among Chinese patients with IgA nephropathy who had mild histologic lesions and persistent proteinuria despite maximal angiotensin blockade, MMF treatment may result in transient and partial remission of proteinuria in the short-term and renoprotection in the long-term.

Topics: Adult; Creatinine; Female; Glomerular Filtration Rate; Glomerulonephritis, IGA; Hong Kong; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Longitudinal Studies; Male; Mycophenolic Acid; Proteinuria; Remission Induction

Proteinuria is an increasingly recognized effect of sirolimus (SRL) therapy in kidney transplant recipients. Predictors of proteinuria after conversion to SRL are not well described, and in particular the risk in African-American (AA) kidney recipients is unknown. We sought to analyze risk factors for proteinuria with SRL therapy in a cohort of 39 patients (44% AA) converted from tacrolimus to SRL at a mean time of 4 months posttransplantation. Patients were maintained on therapy with mycophenolate mofetil while most patients underwent early steroid withdrawal. Urinary protein to creatinine ratio (Up/cr) at a mean of 14 months postconversion increased to > or =500 mg/g in 65% of AAs versus 14% of non-AAs (p = 0.001). Mean arterial blood pressure at the time of conversion and pretransplant proteinuric kidney disease were also predictors of proteinuria after SRL conversion. In conclusion, AAs appear to be at high risk for proteinuria and should be monitored closely after conversion to SRL in calcineurin inhibitor sparing protocols.

Topics: Adult; Female; Humans; Immunosuppressive Agents; Kidney; Kidney Diseases; Kidney Function Tests; Male; Middle Aged; Mycophenolic Acid; Proteinuria; Risk Factors; Sirolimus; Steroids; Tacrolimus

The reasons for kidney allograft failure subsequent to pancreas after kidney (PAK) are multifactorial; therefore, we examined these factors to identify a meaningful risk assessment that could assist in patient selection.. Five transplant centers in New England collaborated for this multiinstitutional retrospective study of 126 PAK transplantation recipients who had a functioning pancreas allograft 7 days after transplantation. Host factors (age at pancreas transplant, gender, body weight, glomerular filtration rate at 3 months pre-PAK and at 3-, 6-, 9-, and 12-month post-PAK, presence of proteinuria, pre- or post-PAK kidney rejection, pancreas rejection, cytomegalovirus disease, and HbA1C at 6-month post-PAK) and transplant factors (time to PAK, use of induction antibody therapy, and combinations of immunosuppressive medications) were assessed in both univariate and multivariate analyses for the primary outcome of kidney allograft failure.. Of the variables assessed, factors associated with kidney allograft loss after PAK include impaired renal function in the 3 months before PAK, proteinuria, the occurrence of a post-PAK kidney rejection episode, and interval between kidney and pancreas transplantation more than 1 year.. In our analysis, post-PAK kidney allograft loss was strongly associated with glomerular filtration rate less than 45 mL/min pre-PAK, K to P interval of over 1 year, pre-PAK kidney rejection episode, and pre-PAK proteinuria. Diabetic candidates for PAK with any of these conditions should be counseled regarding the risk of post-PAK renal transplant failure.

Topics: Adult; Antilymphocyte Serum; Body Weight; Cytomegalovirus Infections; Female; Glomerular Filtration Rate; Glycated Hemoglobin; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Pancreas Transplantation; Predictive Value of Tests; Proteinuria; Renal Replacement Therapy; Risk Assessment; Time Factors; Treatment Failure; Treatment Outcome

Mycoplasma pneumoniae-associated nephritis has been reported in children with various pathological findings. It nevertheless remains an uncommon disease and, within this clinical context, endo-and extracapillary glomerulonephritis in a child has never been described. We report here a case of a 3-year-old girl diagnosed with severe crescentic glomerulonephritis associated with M. pneumoniae infection who presented with nephrotic syndrome and impaired renal function. The serum C3 complement level was initially low but returned to normal after 1 month. Two courses of three methylprednisolone pulses were administered in association with plasmapheresis and, secondarily, mycophenolate mophetil. This treatment regimen led to disease remission and a favorable renal outcome at the 6-month follow-up. However, the treatment guidelines in this situation remain debatable.

Topics: Biomarkers; Child, Preschool; Complement C3-C5 Convertases; Drug Administration Schedule; Female; Glomerulonephritis; Humans; Immunosuppressive Agents; Methylprednisolone; Mycophenolic Acid; Mycoplasma pneumoniae; Nephrotic Syndrome; Plasmapheresis; Pneumonia, Mycoplasma; Proteinuria; Pulse Therapy, Drug; Severity of Illness Index; Time Factors; Treatment Outcome

To observe the efficacy of the combination therapy of mycophenolate mofetil (MMF) and glucocorticoids on steroid-resistant idiopathic membranoproliferative glomerulonephritis (IMPGN) with moderate to heavy proteinuria.. 13 cases were diagnosed as IMPGN by renal biopsy after excluding secondary etiology. 9 patients had heavy proteinuria and another 4 with moderate proteinuria, 9 with hypertension and 11 with decreased renal function. Before MMF therapy, all of them were resistant to treatment of glucocorticoid (prednisone 1 mg/kg/d) for 8 weeks or more. The initial dose of MMF was 1.5 g/d. Patients were followed up every month, including blood pressure, urine protein excretion, liver and kidney function, complete blood count, and adverse events recorded.. At the initiation, the 24-h urine protein excretion was 4.1 +/- 1.4 g, serum creatinine (Scr) 131.0 +/- 44.9 mmol/l, and estimated glomerular filtration rate (eGFR) 63.3 +/- 26.8 ml/min/1.73 m(2). After prednisone therapy for at least 2 months, the 24-h urine protein excretion and eGFR did not change significantly (p > 0.05). After 3 months of the addition of MMF, 24-h urine protein excretion decreased slightly to 3.8 +/- 1.2 g (p < 0.05),Scr decreased to 127.3 +/- 43.7 micromol/l and eGFR elevated to 65.7 +/- 26.8 ml/min/1.73 m(2), (p < 0.05); after 6 months, 24-h urine protein excretion decreased more significantly (2.5 +/- 0.9 g, p < 0.01), with improved kidney function (Scr 97.2 +/- 27.3 mmol/l and eGFR 81.3 +/- 24.2 ml/min/1.73 m(2), p < 0.01); compared with that before MMF treatment. After 12 months, 24-h urine protein excretion decreased further (1.5 +/- 0.6g, p < 0.01) with kidney function remained stable (Scr 95.9 +/- 22.5 micromol/l and eGFR 81.2 +/- 23.8 ml/min/1.73 m(2)).. MMF combined with glucosteroids could effectively decrease proteinuria and improve renal function on steroid-resistant IMPGN. Further study with a large sample is needed to evaluate the efficacy and safety of MMF in the treatment of IMPGN.

Topics: Adult; Drug Resistance; Drug Therapy, Combination; Female; Follow-Up Studies; Glomerular Filtration Rate; Glomerulonephritis, Membranoproliferative; Glucocorticoids; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Prednisone; Prospective Studies; Proteinuria; Treatment Outcome; Young Adult

Lupus nephritis (LN) is an immune inflammation of kidneys caused by systemic lupus erythematosus (SLE), a chronic inflammatory disease that affects the body's immune system. Aim of this study was to analyze clinical manifestation and treatment results of patients with LN. Forty one patients with clinical signs of LN were included in the study. Mean age of patients was 31.9+/-12.1 years in the moment of first diagnosis of LN, with female-male ratio 8:1. Renal disease was pathohistologically (PTH) verified in 53.7% of patients (4 pts with class III, 17 pts with class IV, one pt with class V of lupus nephrites). Patients with high nephrotic proteinuria were treated with pulse dose of methylprednisolone and pulse doses of cyclophosphamide (CYC) in induction therapy. Corticosteroid and CYC were continued according to treatment protocol. The other group of LN patients with lower nephrotic proteinuria was treated with mycophenolate mofetil (MMF) in induction therapy at a dose of 2x1 g/day for six months, and than in maintenance 2x0.5 g/day. The patients with non-nephrotic proteinuria and normal renal function were treated with oral prednisolone 0.75-1 mg/kg/day in a single morning dose, and then gradually reduced to the dose of maintenance. The mean time of patient's follow-up was 10.9+/-4.1 years. Partial renal remission was accomplished in 29.2% pts, and complete remission in 60.9% pts for period of 17.2+/-13.3 months from the beginning of the treatment. Duration of complete renal remission was 30.1+/-19.1 months. During the period of follow-up, 29.3% pts developed at least one nephritic flare and were treated again. These results confirmed that the aggressive form of lupus nephritis should be treated associating cyclophosphamide with corticosteroids therapeutical regiment. MMF is a new promising immunosuppressive drug for a treatment of this serious disease.

Topics: Adult; Cyclophosphamide; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Inflammation; Lupus Nephritis; Male; Methylprednisolone; Mycophenolic Acid; Proteinuria; Remission Induction; Time Factors; Treatment Outcome

In large-scale clinical trials, the proliferation signal inhibitor (PSI) everolimus (EVL) combined with cyclosporine (CsA) and steroids, has been shown to be efficacious among de novo renal transplant recipients. Development of proteinuria has been shown to be an important predictor of renal dysfunction after conversion from CsA to a PSI-based regimen, and a key marker of allograft disease progression. Whether EVL de novo treatment is associated with a similar proteinuric effect is still under investigation.. We compared the development of proteinuria among a cohort of 24 renal transplant recipients who were prescribed EVL (3 mg/d; n = 12; high-dose group) or 1.5 mg/d (n = 12; standard-dose group), in association with CsA, versus third control cohort of 12 patients who received mycophenolate mofetil (control group). EVL doses were adjusted to achieve trough blood levels of 3-8 ng/mL and 8-12 ng/mL among the standard and high-dose groups, respectively. We assessed renal function and protein excretion over a 2-year observation.. The high-dose group showed a trend toward greater proteinuria than the standard-dose on control groups. They showed significantly greater proteinuria from 9 months until 2 years; 0.86 +/- 0.5, 0.5 +/- 0.3, 0.47 +/- 0.2 g/24 h (P = .03 and P = .02, respectively, at 24 months). Mean proteinuria significantly correlated with mean EVL doses (n = .73; P = .0001). Concomitantly, the estimated glomerular filtration rate (eGFR) was significantly lower among patients treated with EVL 3.0 versus 1.5 mg/d (53.7 +/- 24 vs 73.04 +/- 17.6 mL/min; P = .037). Among patients in the standard-dose, the eGFR was consistently higher than the control group (62.6 +/- 29 mL/min).. EVL/CsA therapy is a safe alternative regimen for de novo renal transplant recipients. Higher EVL doses are correlated with greater increases in proteinuria. The standard EVL dose seems to be useful treatment strategy to prevent acute rejection episodes, with a better renal prognosis in the long term.

Topics: Adult; Cohort Studies; Dose-Response Relationship, Drug; Everolimus; Female; Follow-Up Studies; HLA Antigens; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Pilot Projects; Prognosis; Proteinuria; Sample Size; Sirolimus

Recent evidence of a high incidence of proteinuria among de novo sirolimus-based regimens has been reported among renal transplant patients at short-term follow-up. We report on long-term evaluation of proteinuria among patients maintained on such regimen.. Between May 2001 and January 2003, 132 patients received a renal allograft from a living donor and were randomized to 2 groups (steroids/sirolimus/tacrolimus, n=65) and (steroids/sirolimus/mycophenolate mofetil, n=67): Both received basiliximab induction. Retrospective review of those patients was performed, 5 years posttransplant with particular emphasis on the incidence of proteinuria.. The 5-year incidence of proteinuria was 29.2% and 38.8% among sirolimus/tacrolimus and sirolimus/mycophenolate mofetil group. Single DR-matched patients (P = .016) and the incidence of acute rejection (P = .039) were associated with significantly higher incidence of proteinuria. Moreover, the presence of mesangial matrix increased (P = .015), and glomerulosclerosis (P = .014), in 1-year protocol biopsies, was found to have a positive predictive value for current and future incidences of proteinuria. Proteinuria was found to be associated with significant inferior graft outcome. Recurrent original kidney disease, de novo glomerulopathy, and acute transplant glomerulopathy were responsible for early cases of nephrotic range proteinuria (first 2 years), while cases presented later were attributed to chronic allograft nephropathy.. Proteinuria has become a recognized, serious event of primarily sirolimus-treated renal transplants patients, which is most probably of glomerular origin. It has been shown that proteinuria exerts a bad prognostic effect upon graft function and subsequent graft survival at 5-year follow-up.

Topics: Adult; Biopsy; Chi-Square Distribution; Drug Therapy, Combination; Egypt; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Incidence; Kaplan-Meier Estimate; Kidney Transplantation; Living Donors; Male; Mycophenolic Acid; Proteinuria; Randomized Controlled Trials as Topic; Retrospective Studies; Risk Assessment; Risk Factors; Sirolimus; Steroids; Tacrolimus; Time Factors; Transplantation, Homologous; Treatment Outcome; Young Adult

Secondary amyloidosis is an unusual complication of systemic lupus erythematosus (SLE). We report the case of a 60-year-old woman with SLE and secondary amyloidosis who developed class III proliferative lupus nephritis 13 years after the onset of amyloid nephropathy. The patient was treated with mycophenolate mofetil (1.5 g/day) with a significant improvement in proteinuria.

Topics: Amyloid; Amyloidosis; Anti-Inflammatory Agents, Non-Steroidal; Female; Humans; Kidney; Kidney Glomerulus; Lupus Nephritis; Middle Aged; Mycophenolic Acid; Proteinuria; Treatment Outcome

The purpose of this study is to evaluate the effectiveness and safety of mycophenolate mofetil (MMF) for inducing and/or maintaining remission of lupus nephritis (LN). This is a retrospective study of 25 LN patients consecutively treated with MMF. The primary outcome was complete renal remission (CR) defined by urine protein/creatinine ratio < or =0.5 g/g and inactive urine sediment and serum creatinine within <15% above baseline. For induction, 21 episodes of active, moderate to severe LN were treated with MMF. Twelve cases (57%) achieved CR over a median of 8.5 months. Of 13 patients who had LN for <12 months and took > or =2 g/day of MMF, 11 achieved CR, compared to one out of the eight patients who did not meet both criteria (p = 0.0022). For maintenance therapy, 15 patients received MMF for a median of 20 months (range 5-55 months). Two patients (13%) experienced renal flares while taking MMF. Most adverse events were transient and did not require change in therapy. This study suggests that MMF is an effective treatment for both induction and maintenance of remission of moderate to severe LN with a relatively favorable safety profile. Early treatment and a dose > or =2 g/day are essential for optimal outcome. CR may take >6 months.

Topics: Adolescent; Adult; Anti-Inflammatory Agents, Non-Steroidal; Creatinine; Drug Therapy, Combination; Female; Humans; Lupus Nephritis; Male; Middle Aged; Mycophenolic Acid; Prednisone; Proteinuria; Remission Induction; Retrospective Studies; Treatment Outcome; Young Adult

Experimental data and few clinical non-randomized studies have shown that inhibition of the renin-angiotensin system by angiotensin-converting enzyme (ACE) associated or not with the use of mycophenolate mofetil (MMF) could delay or even halt the progression of chronic allograft nephropathy (CAN). In this retrospective historical study, we investigated whether ACE inhibition (ACEI) associated or not with the use of MMF has the same effect in humans as in experimental studies and what factors are associated with a clinical response. A total of 160 transplant patients with biopsy-proven CAN were enrolled. Eighty-one of them were on ACE therapy (G1) and 80 on ACEI_free therapy (G2). Patients were further stratified for the use of MMF. G1 patients showed a marked decrease in proteinuria and stabilized serum creatinine with time. Five-year graft survival after CAN diagnosis was more frequent in G1 (86.9 vs 67.7%; P < 0.05). In patients on ACEI-free therapy, the use of MMF was associated with better graft survival. The use of ACEI therapy protected 79% of the patients against graft loss (OR = 0.079, 95%CI = 0.015-0.426; P = 0.003). ACEI and MMF or the use of MMF alone after CAN diagnosis conferred protection against graft loss. This finding is well correlated with experimental studies in which ACEI and MMF interrupt the progression of chronic allograft dysfunction and injury. The use of ACEI alone or in combination with MMF significantly reduced proteinuria and stabilized serum creatinine, consequently improving renal allograft survival.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Biopsy; Chronic Disease; Creatinine; Drug Synergism; Drug Therapy, Combination; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Male; Mycophenolic Acid; Proteinuria; Retrospective Studies; Severity of Illness Index

Anti-mTOR may induce proteinuria when utilized after renal transplantation. Little is known about the pathogenesis and composition of proteinuria. To clarify this unresolved aspect, we analyzed urinary protein composition utilizing an integrated proteomics approach, including quantitative assays, 2-dimensional electrophoresis, MALDI-TOF, and Western blots among 48 renal transplant recipients treated with everolimus (EVL; n = 31) or enteric-coated mycophenolic acid (EC-MPA; n = 17). High (>3 g/d) or intermediate levels of proteinuria (1-3 g) developed in 12 EVL patients (39%) compared with 4 subjects (23%) in the EC-MPA group. Proteinuria, which started during the first 2 days after EVL, tended to reduce during the follow-up. Quantitative proteomics showed an increase in low molecular proteins beta2 microglobulin (P < .001) and alpha1 microglobulin (P < .025). Qualitative proteomics showed a marked increase among all urinary components in EVL and EC-MPA patients. Major changes involved typical components of glomerular damage: albumin, Zn-alpha1 glycoprotein, alpha2HS glycoprotein, and leucine-rich alpha2 glycoprotein. In addition, we observed specific biomarkers for EVL: clusters of alpha1-antitrypsin fragments and monoclonal lambda chains. In conclusion, EVL induced proteinuria of a mixed glomerular and tubular origin that correlated with the start of treatment and reached nephrotic ranges in few cases. The specific urinary markers may reflect renal alterations related to the transplant or specific alterations associated with the drug.

Topics: Adult; Everolimus; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Glomerulus; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Proteinuria; Sirolimus

Hypertensive disorders of pregnancy, including preeclampsia (PE), affect approximately 7-10% of pregnancies in the US. Clinical and experimental studies strongly suggest that the maternal immune system plays a role in the development of these disorders; however, few therapeutic options exist aside from delivery.. Using a deoxycorticosterone acetate (DOCA)/salt-low renin rat model, which exhibits hypertension, proteinuria, endothelial dysfunction, and intrauterine growth restriction (IUGR), we measured serum cytokine levels as an indication of immune system activation. In addition, we suppressed the immune system with either azathioprine (Aza) or mycophenolate mofetil (MMF) during the second half of pregnancy to determine whether the these symptoms could be ameliorated.. Our results demonstrate that serum T helper-1 (Th1)-type inflammatory cytokines interleukin (IL)-2, IL-12, interferon-gamma (IFNgamma), and RANTES were significantly elevated in hypertensive pregnant rats while the Th2-type cytokine IL-4 was elevated in normal pregnant animals. Either Aza or MMF significantly attenuated the hypertension, proteinuria, and endothelial dysfunction as well as the increased proinflammatory Th1 cytokine profile in pregnant rats treated with DOCA/salt, and had no effect on these parameters in normal pregnant rats.. These data strongly suggest that maternal immune system activation plays a role in the development of pregnancy-induced hypertension (PIH).

Topics: Animals; Azathioprine; Blood Pressure; Cytokines; Desoxycorticosterone; Disease Models, Animal; Endothelium, Vascular; Female; Fetal Growth Retardation; Hypertension, Pregnancy-Induced; Immunosuppression Therapy; Immunosuppressive Agents; Mycophenolic Acid; Pregnancy; Proteinuria; Rats; Rats, Sprague-Dawley

In our center, systemic lupus erythematosus nephritis is routinely treated with an oral cyclophosphamide (POCY) regimen. POCY is easy to administer and less expensive than intravenous cyclophosphamide (IVCY) as it is currently used in the United States; however, the use of POCY has declined in favor of IVCY. Our experience with POCY suggests that it is well tolerated and consistently associated with good long-term outcomes. Here we report this experience to build a case for maintaining POCY as a therapeutic option in lupus nephritis.. This is a single-center, retrospective analysis of the outcome of 46 patients who had systemic lupus erythematosus with nephritis and were treated with POCY between 1995 and 2006. POCY was given for 2 to 4 mo at a dosage of 1.0 to 1.5 mg/kg ideal body weight. After completing POCY, the patients received either azathioprine or mycophenolate mofetil.. Median follow-up was 23.5 mo, and median duration of POCY was 4 mo (range 1 to 16 mo). Durable complete or partial remission of proteinuria was achieved in 32 (70%) patients, whereas 5 (11%) progressed to ESRD. Outcomes were comparable in black and white individuals. Adverse effects occurred in fewer than 10% of the cohort, and only four patients discontinued POCY.. These results suggest that sequential therapy of POCY followed by azathioprine or mycophenolate mofetil is comparable to IVCY regimens but that efficacy may not be affected by race.

Topics: Administration, Oral; Adult; Aged; Azathioprine; Black People; Creatinine; Cyclophosphamide; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Lupus Nephritis; Male; Middle Aged; Mycophenolic Acid; Proteinuria; Remission Induction; Retrospective Studies; White People; Young Adult

Graves' disease can be associated with other autoimmune disorders. Primary systemic sclerosis (PSS) is such a disease characterised by multi-organ fibrosis. Abnormal thyroid antibody titres and hypothyroidism as well as hyperthyroidism have been observed in PSS patients. Specific and idiopathic inflammatory disorders are an important differential diagnosis in Graves'orbitopathy (GO). Mycophenolate mofetil (MM) is an immunosuppressive drug which depletes guanosin nucleotides in proliferating B-and T-lymphocytes. We describe the effect of MM on the endocrine orbitopathy of a patient with PSS.

Topics: Azathioprine; Bosentan; Cyclophosphamide; Drug Therapy, Combination; Female; Glucocorticoids; Graves Disease; Humans; Hypertension, Pulmonary; Immunoglobulins, Intravenous; Immunosuppressive Agents; Methotrexate; Middle Aged; Mycophenolic Acid; Proteinuria; Raynaud Disease; Scleroderma, Systemic; Sulfonamides

Calcineurin-inhibitor therapy can lead to renal dysfunction in heart transplantation patients. The novel immunosuppressive (IS) drug sirolmus (Srl) lacks nephrotoxic effects; however, proteinuria associated with Srl has been reported following renal transplantation. In cardiac transplantation, the incidence of proteinuria associated with Srl is unknown. In this study, long-term cardiac transplant patients were switched from cyclosporine to Srl-based IS. Concomitant IS consisted of mycophenolate mofetil +/- steroids. Proteinuria increased significantly from a median of 0.13 g/day (range 0-5.7) preswitch to 0.23 g/day (0-9.88) at 24 months postswitch (p = 0.0024). Before the switch, 11.5% of patients had high-grade proteinuria (>1.0 g/day); this increased to 22.9% postswitch (p = 0.006). ACE inhibitor and angiotensin-releasing blocker (ARB) therapy reduced proteinuria development. Patients without proteinuria had increased renal function (median 42.5 vs. 64.1, p = 0.25), whereas patients who developed high-grade proteinuria showed decreased renal function at the end of follow-up (median 39.6 vs. 29.2, p = 0.125). Thus, proteinuria may develop in cardiac transplant patients after switch to Srl, which may have an adverse effect on renal function in these patients. Srl should be used with ACEi/ARB therapy and patients monitored for proteinuria and increased renal dysfunction.

Topics: Adrenal Cortex Hormones; Antihypertensive Agents; Clinical Trials as Topic; Drug Therapy, Combination; Environmental Monitoring; Female; Heart Transplantation; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunosuppressive Agents; Male; Mycophenolic Acid; Patient Selection; Prospective Studies; Proteinuria; Sirolimus; Survival Analysis

Mycophenolate mofetil is an immunosupressive agent used in transplantation and subsequently in a variety of autoimmune conditions. It inhibits both B and T lymphocyte proliferation, and also has nonimmune effects on the kidney. The major experience in systemic lupus erythematosus has focused on proliferative lupus nephritis.. In our study we treated 8 female patients with proliferative lupus nefritis with combination therapy of prednisone (1 mg/kg body weight) and mycophenolate mofetil (2 g per day). Complete remission was defined as a value for urinary protein excretion that was less than 0.5 g per 24 hours, with normal urinary sediment, a normal serum albumin concentration and improved or stable serum creatinine. Partial remission was defined as a daily proteinuria below 2 g in a previously nephrotic patient or minimum 30% from starting values, with normal urinary sediment, serum albumin of minimum 30 g/L and stable serum creatinine.. Two patients had a complete remission after 7 and 2 months respectively. Five patients had a partial remission after 5.2+/-4.3 months of therapy. One patient did not react on therapy. There were no side effects during the course of therapy.. Considering the fact that 7/8 patients have had nephrotic range proteinuria and that 50% of patients were refractory on standard induction therapy, results of this study are good indicator of value of mycophenolate mofetil in the terapy of proliferative forms of lupus nephritis.. Mycophenolate mofetil gives satisfactory results in the treatment of proliferative forms of lupus nephritis with minimal side effects.

Topics: Adult; Female; Humans; Immunosuppressive Agents; Lupus Nephritis; Mycophenolic Acid; Proteinuria; Remission Induction

The goal of this study was to test the hypothesis that renal infiltration of immune cells in Dahl S rats on increased dietary sodium intake contributes to the progression of renal damage, decreases in renal hemodynamics, and development of hypertension. We specifically studied whether anti-immune therapy, using mycophenolate mofetil (MMF), could help prevent increases in renal NF-kappaB activation, renal infiltration of monocytes/macrophages, renal damage, decreases in glomerular filtration rate (GFR) and renal plasma flow, and increases in arterial pressure. Seventy-four 7-to 8-wk-old Dahl S, Rapp strain rats were maintained on an 8% Na, 8% Na + MMF (20 mg.kg(-1).day(-1)), 0.3% Na, or 0.3% Na + MMF diet for 5 wk. Arterial and venous catheters were implanted at day 21. By day 35, renal NF-kappaB in 8% Na rats was 47% higher than in 0.3% Na rats and renal NF-kappaB was 41% lower in 8% Na + MMF rats compared with the 8% Na group. MMF treatment significantly decreased renal monocyte/macrophage infiltration and renal damage and increased GFR and renal plasma flow. In high-NA Dahl S rats mean arterial pressure increased to 182 +/- 5 mmHg, and MMF reduced this arterial pressure to 124 +/- 3 mmHg. In summary, in Dahl S rats on high sodium intake, treatment with MMF decreases renal NF-kappaB and renal monocyte/macrophage infiltration and improves renal function, lessens renal injury, and decreases arterial pressure. This suggests that renal infiltration of immune cells is associated with increased arterial pressure and renal damage and decreasing GFR and renal plasma flow in Dahl salt-sensitive hypertension.

Topics: Animals; Blood Pressure; Disease Models, Animal; Dose-Response Relationship, Drug; Glomerular Filtration Rate; Glutathione; Heart Rate; Hypertension; Immunosuppressive Agents; Kidney; Kidney Diseases; Macrophages; Male; Mycophenolic Acid; NF-kappa B; Proteinuria; Rats; Rats, Inbred Dahl; Renal Circulation; Sodium Chloride, Dietary; Superoxide Dismutase; Superoxides; Time Factors; Vascular Resistance

Persistent proteinuria in patients with quiescent lupus can result from membranous lupus nephritis and/or glomerular scarring following previous flares. This pilot study examined the effects of tacrolimus over two years in six patients with membranous/inactive lupus nephritis and persistent proteinuria despite angiotensin inhibition/blockade. Tacrolimus treatment reduced proteinuria and increased serum albumin (time effect, P = 0.047 and 0.032 respectively). Compared with baseline levels, proteinuria improved by more than 50% in five patients (83.3%) and hypoalbuminaemia was corrected in four patients. The efficacy was most prominent in four patients with biopsy-proven membranous lupus nephritis, whose protienuria improved by over 80%. One patient developed biopsy-proven chronic nephrotoxicity after 10 months of tacrolimus treatment, despite non-excessive blood levels. These data suggest that tacrolimus is an effective treatment for proteinuria due to membranous lupus nephritis, but should probably be reserved for patients who are refractory to other non-nephrotoxic treatments, in view of the potential risk of subclinical nephrotoxicity.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Antibodies, Antinuclear; Autoantigens; Blood Glucose; Blood Pressure; Complement C3; Creatinine; DNA; Drug Evaluation; Drug Resistance; Female; Humans; Hypoalbuminemia; Immunosuppressive Agents; Kidney Diseases; Lipids; Lupus Nephritis; Male; Middle Aged; Mycophenolic Acid; Pilot Projects; Prednisolone; Proteinuria; Retrospective Studies; Serum Albumin; Tacrolimus; Treatment Outcome

An eight-yr-old combined liver and kidney transplant recipient for hyperoxaluria type I developed significant proteinuria and hypertension after conversion of a Tacrolimus, MMF, and corticosteroids-based immunosuppression to Sirolimus, low-dose Tacrolimus, and corticosteroids six and a half yr after the transplant for chronic allograft nephropathy. There was only one class I HLA match and the recipient had multiple blood exposures prior to transplantation. The patient was treated with combined hemodialysis and peritoneal dialysis while awaiting transplantation to reduce the oxalate load. A renal biopsy revealed a de novo transplant glomerulopathy that was associated with specific HLA antibodies unrelated to the donor (HLA DR 17 and 18). After reintroduction of MMF, these antibodies became undetectable and the proteinuria completely resolved. We hypothesize that HLA antibodies may cause transplant glomerulopathy even if they are not donor-specific. Their production appears more susceptible to MMF therapy. A thorough work-up of new-onset proteinuria after conversion to Sirolimus should be performed, including an immunological work-up and a renal biopsy.

Topics: Biopsy; Child; Chronic Disease; HLA Antigens; Humans; Immunosuppressive Agents; Kidney Transplantation; Liver Transplantation; Male; Mycophenolic Acid; Proteinuria; Sirolimus

Hypertension is a likely consequence of chronic lead exposure in humans, especially in association with reduced renal function and in high risk populations. Numerous studies have demonstrated that oxidative stress plays an important role in the pathogenesis of experimental lead-induced hypertension and we have shown recently that tubulointerstitial immune cell infiltration is a feature of chronic low-dose lead exposure. Since oxidative stress, renal inflammation, and angiotensin activity are closely linked characteristics in experimental models of hypertension, we decided to investigate whether lead-induced hypertension would be ameliorated by suppressing renal inflammation with the immunosuppressive drug mycophenolate mofetil (MMF). We studied rats exposed for 14 wk to lead acetate (100 ppm in the drinking water) that, in addition, received either MMF, 20 mg.kg(-1).day(-1) by gastric gavage (Pb.MMF group, n = 12) or vehicle (Pb group, n = 12). Control rats received MMF alone (n = 5) or neither lead nor MMF (n = 6). All rats were killed at the end of the experiment. Low-dose lead exposure resulted in mild to moderate tubular cell damage and a progressive increment in blood pressure, oxidative stress, interstitial accumulation of lymphocytes and macrophages, NF-kappaB activation, and increased renal angiotensin II level. The administration of MMF suppressed the tubulointerstitial accumulation of lymphocytes and macrophages and prevented the hypertension, oxidative stress, and NF-kappaB activation and reduced the heightened renal angiotensin content associated with chronic lead exposure. We conclude that interstitial inflammation plays an important role in lead-induced hypertension.

Topics: Angiotensin II; Animals; Blood Pressure; Body Weight; Creatinine; Hypertension; Immunosuppressive Agents; Inflammation; Kidney Diseases; Lead; Lymphocytes; Macrophages; Male; Malondialdehyde; Mycophenolic Acid; Oxidative Stress; Proteinuria; Rats; Rats, Sprague-Dawley; Superoxides; Transcription Factor RelA

Idiopathic membranous nephropathy (IMN) is one of the most common causes of primary nephrotic syndrome in adults. However, it is a relatively rare entity in the pediatric population and there is a paucity of data about the incidence, prognosis, and optimal treatment of IMN in children and adolescents. We conducted this study to evaluate pediatric patients with IMN in order to clarify the presentation, response to therapy, and clinical outcome.. A retrospective chart review was performed on patients identified with biopsy-proven IMN between 1988-2005. Patients with systemic lupus erythematosus or hepatitis-related lesions were excluded. The following data were tabulated: age, gender, ethnicity, presenting clinical and laboratory findings, proteinuria in a first morning urine specimen, estimated glomerular filtration rate (GFRe), histopathology, type and duration of treatment, and clinical status at final evaluation.. 13 cases of IMN were identified out of 460 renal biopsies performed for evaluation of primary kidney disease during the study interval. Mean age was 9.6 +/- 4.6, gender 6 M:7 F, ethnicity 8 W:2 B:3 H. At the initial visit hematuria was present in 9 patients, edema in 5, nephrotic-range proteinuria in 5, and hypertension in 3. Mean urinary protein:creatinine ratio 3.3 +/- 2.5 and all patients had a normal GFRe. Classic glomerular findings of IMN were seen in all renal specimens, with concomitant interstitial changes in 2 cases. Treatment included an angiotensin converting enzyme inhibitor or angiotensin receptor blocker in 11 cases. Most patients were also given immunosuppressive medications - prednisone in 10, a calcineurin inhibitor in 5, and mycophenolate mofetil or azathioprine in 3 patients. At the last follow-up, 42 +/- 35 months after the diagnostic biopsy, 7 children were hypertensive and the urine protein:creatinine ratio was 2.3 +/- 3.1. The mean GFRe was 127 +/- 57 mL/min/m2. Three patients had Chronic Kidney Disease Stage 3, all of whom were also hypertensive.. IMN is a rare but serious glomerulopathy in pediatrics. We estimate that it accounts for approximately 3% of renal biopsies. Long-term prognosis is guarded because approximately 50% of patients may have evidence of progressive kidney disease.

Topics: Adolescent; Biopsy; Child; Child, Preschool; Female; Glomerular Filtration Rate; Glomerulonephritis, Membranous; Humans; Hypertension; Immunosuppressive Agents; Kidney; Kidney Failure, Chronic; Male; Mycophenolic Acid; Prednisone; Prognosis; Proteinuria; Retrospective Studies; Time Factors; Treatment Outcome

The usefulness of mycophenolate mofetil (MMF) levels in stable kidney transplant patients is not well known. We measured MMF trough levels in 137 adult kidney recipients with more than 1 year of stable graft function. The MMF dose was adjusted according to hematological or gastrointestinal toxicity, it was 500 mg in 22 (16%) patients; 750 mg in 22 (16%); 1000 mg in 69 (50.5%); 1500 mg in 15 (11%); and 2000 mg in 9 (6.5%). We analyzed the total dose, virgule dose/kg, and MMF levels in relation to efficacy parameters (creatinine, proteinuria) and hematological toxicity (erythrocytes, leukocytes, and platelets) at the time of MMF level determinations and 3 months thereafter. Statistical analyses were performed with SSPS 12.0, including sensitivity and specificity analyses by ROC. Mean MMF levels were 3.68 mg/L (Pc25, 1.6-Pc75, 4.4 mg/L) with significant differences according to dose (P < .001). Trough MMF levels did not have discriminatory capacity in the area under the ROC for anemia, renal failure, or proteinuria at the time of determination or 3 months later. The percentage of patients without proteinuria was high among patients with MMF levels between 1.6 and 4.4 mg/L. The MMF levels were low in patients who had a major increase in creatinine (1.6 vs 3.8 mg/L, P < .05). In stable renal transplant patients the levels of MMF were related to the administered dose, and they are higher than those previously described in patients with less than a year follow-up with a functioning kidney. They did not have discriminatory value at the time of determination or 3 months later. Nevertheless, low MMF levels could help recognize patients at risk of developing chronic nephropathy.

Topics: Adult; Aged; Aged, 80 and over; Creatinine; Humans; Immunosuppressive Agents; Kidney Transplantation; Middle Aged; Mycophenolic Acid; Proteinuria

We report a Caucasian boy of Italian descent with congenital nephrotic syndrome of the Finnish type (NPHS1, CNF, MIM 256300) who developed recurrence of proteinuria and hypoalbuminemia on the seventh post-operative day following living related renal transplantation from his paternal aunt. The allograft biopsy was normal except for effacement of podocyte foot processes on electron microscopy. He was treated by the substitution of mycophenolate mofetil with cyclophosphamide for 12 weeks, in addition to cyclosporine, prednisone and daclizumab. His proteinuria resolved quickly following the initiation of cyclophosphamide treatment, and he remains in remission 4 years after receiving his transplant. His native and allograft kidneys were evaluated for nephrin expression by immunohistochemistry, DNA analysis for the NPHS1 mutation, serum for the presence of auto-antibodies to nephrin by both enzyme-linked immunosorbent assay (ELISA) and fetal glomeruli immunofluorescence assay, and serum for glomerular permeability to albumin (Palb) activity using a functional in vitro assay for Palb. Nephrin expression was completely absent in the native kidney, while it was decreased in the allograft compared with normal. DNA analysis of the NPHS1 gene revealed mutations 3248G>T and 3250delG in exon 24, causing G1083V and 1084Vfs, respectively, inherited from his father, and 3478C>T in exon 27, that leads to R1160X, inherited from his mother. Serum was negative for auto-antibodies to nephrin. Interestingly, the Palb activity was increased at the time of recurrence of proteinuria following transplantation (Palb 0.73+/-0.10) and remained elevated when retested more than 3 years later (Palb 0.54+/-0.09). This is the first report of increased Palb activity in recurrence of proteinuria following transplantation in NPHS1. We speculate the role of increased Palb activity in the recurrence of proteinuria following transplantation in NPHS1.

Topics: Albumins; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Autoantibodies; Capillary Permeability; Cyclophosphamide; Cyclosporine; Daclizumab; Humans; Hypoalbuminemia; Immunoglobulin G; Immunosuppressive Agents; Infant, Newborn; Kidney Glomerulus; Kidney Transplantation; Living Donors; Male; Membrane Proteins; Mutation; Mycophenolic Acid; Nephrectomy; Nephrotic Syndrome; Peritoneal Dialysis; Prednisone; Proteinuria; Recurrence

The objective of this study was to identify clinical predictors of response to initial mycophenolate mofetil (MMF) therapy for membranous lupus nephritis (MLN). We observed the clinical outcomes of patients in the Hopkins Lupus Cohort within the first year of initiation of treatment with MMF therapy for newly diagnosed MLN, classified according to the new International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 classification. Complete renal remission was defined as proteinuria less than 500 mg/24 hours. Demographic, clinical, treatment and laboratory data were examined for their association with renal remission. Twenty-nine MLN patients treated with MMF were identified. Eleven (38%) patients achieved complete renal remission by 12 months. Of those taking hydroxychloroquine, 7/11 (64%) were in remission within 12 months compared to only 4/18 (22%) of those not on hyroxychloroquine (P = 0.036 based on a log-rank test). This association persisted after controlling for the presence of anti-ds-DNA (P = 0.026). Our results provide evidence that hydroxychloroquine has a benefit for renal remission when MMF is used as the initial therapy for MLN. Although hydroxychloroquine is frequently stopped in patients with lupus nephritis, this study suggests it should be started or maintained.

Topics: Adolescent; Adult; Angiotensin-Converting Enzyme Inhibitors; Anti-Inflammatory Agents, Non-Steroidal; Biopsy; Clinical Trials as Topic; Cohort Studies; Drug Therapy, Combination; Female; Humans; Hydroxychloroquine; Immunosuppressive Agents; Lupus Nephritis; Male; Mycophenolic Acid; Prednisone; Prognosis; Proteinuria; Remission Induction; Retrospective Studies; Severity of Illness Index; Treatment Outcome

A case of a young adult with refractory nephrotic syndrome due to focal segmental glomerulosclerosis is reported. Several treatments had been used without success including steroids, cyclophosphamide, cyclosporine A, tacrolimus, and mycophenolate mofetil. Immunoadsorption was performed as a last resort to manage the nephrotic syndrome, which led to a drastic urinary protein reduction. We review the literature supporting immunoadsorption in primary focal segmental glomerulosclerosis.

Topics: Adult; Anemia, Megaloblastic; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Azathioprine; Blood Proteins; Combined Modality Therapy; Cyclophosphamide; Drug Resistance; Glomerulosclerosis, Focal Segmental; Humans; Immunosorbent Techniques; Immunosuppressive Agents; Male; Mycophenolic Acid; Nephrotic Syndrome; Plasmapheresis; Proteinuria; Sepharose; Staphylococcal Protein A; Tacrolimus

Long term cyclophosfamide combinated steroids therapy improves renal survival in patients with Proliferate Lupus Nephritis, with considerable toxic effects. In lately years MMF, a immune suppressor used in transplant, seems to be effective in selected cases of Lupus Nephritis.. We will describe six patients with Lupus Nephritis class IV and V (OMS Classification), that what different causes they must be treated with MMF like rescue drug. This stabilizes the renal function, controls LES activity and allows reductions or end of corticoids.. In tree cases we achievement total remission, two show partial remission and we had a fail because plaquetopenia and severe leucopenia with serious sepsis to give rise to neumopaty; this patient broke off the treatment. One presented Zoster Herpes that was treated with Aciclovir and temporary treatment break off.. MMF was effective to get remission in NL and maintain inactive LES, so it must to be considering as rescue therapy, or maintenance treatment after cyclosphosfamide induction. In patients where fertility is important must be considering like elective drug. Is necessary long time patients follow up to asses' effectiveness in renal survival, like cyclophosfamide.

Topics: Adult; Biopsy; Creatinine; Female; Hematuria; Humans; Immunosuppressive Agents; Lupus Nephritis; Middle Aged; Mycophenolic Acid; Proteinuria; Remission Induction; Salvage Therapy; Treatment Outcome

Tubulointerstitial inflammation and fibrosis are hallmarks of chronic progressive renal diseases. To characterize the functional interaction between cell infiltration and matrix expansion, this study compared the immunosuppressant mycophenolate mofetil (MMF), intended as primarily anti-inflammatory intervention, the angiotensin-converting enzyme inhibitor enalapril, intended as primarily an anti-fibrotic drug, and a combination of both as anticipated anti-inflammatory/anti-fibrotic intervention. The model used was anti-thy1-induced chronic-progressive glomerulosclerosis (cGS) in the rat, where a brief anti-thy1-induced glomerular injury progresses spontaneously toward tubulointerstitial fibrosis and renal insufficiency. cGS was induced by injection of anti-thy1 antibody into uninephrectomized Wistar rats. One week after disease induction, animals were randomly assigned to the following groups: cGS, cGS plus MMF (20 mg.kg body wt(-1).day(-1)), cGS plus high-dose enalapril (12 mg.kg body wt(-1).day(-1)), and cGS plus both. At week 16 after disease induction, MMF or enalapril alone reduced signs of chronic renal disease significantly and similarly compared with the untreated cGS group. Variables measured included proteinuria, blood pressure, tubulointerstitial and glomerular matrix accumulation, expression of transforming growth factor-beta(1), fibronectin, and plasminogen activator inhibitor-1, infiltration of lymphocytes and macrophages, plasma creatinine and urea levels, and glomerular filtration rate. Combined MMF and enalapril treatment was not superior to single therapy. In conclusion, MMF slows the progression of chronic renal fibrosis and renal insufficiency as effectively as high-dose enalapril in the anti-thy1-induced chronic-progressive glomerulosclerosis model. The dual anti-inflammatory/anti-fibrotic intervention does not yield additive renoprotective effects, indicating that MMF and enalapril interfere with similar or very closely related pathways involved in progression of renal disease.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Cell Count; Blood Pressure; Body Weight; Disease Progression; Drug Interactions; Eating; Enalapril; Fibronectins; Fibrosis; Glomerulosclerosis, Focal Segmental; Immunohistochemistry; Immunosuppressive Agents; Kidney Diseases; Kidney Function Tests; Male; Mycophenolic Acid; Nephrectomy; Plasminogen Activator Inhibitor 1; Proteinuria; Rats; Rats, Wistar; Thy-1 Antigens; Transforming Growth Factor beta; Transforming Growth Factor beta1

To assess the indications, efficacy, and tolerability of mycophenolate mofetil (MMF) in patients with systemic lupus erythematosus (SLE) resistant to other immunosuppressive therapy.. Records of 93 patients with SLE were retrospectively reviewed. Seven patients were excluded. The remaining 86 patients received other immunosuppressive drugs before MMF. Efficacy was measured by changes in daily oral prednisolone dose, European Consensus Lupus Activity Measurement Index (ECLAM), erythrocyte sedimentation rate (ESR), C-reactive protein, and dsDNA antibody titer. In renal patients, changes in serum creatinine, creatinine clearance, chromium-51 EDTA glomerular filtration rate (EDTA-GFR), and 24 hour urine protein excretion were also evaluated.. Indications for MMF were mainly renal involvement (59% of patients), uncontrolled disease activity (14%), and other SLE related manifestations (13%). Overall, we found a significant reduction in the steroid dosage, ECLAM, ESR, and anti-dsDNA antibody titer. Renal patients (n = 35) showed a significant reduction in urinary 24 hour protein excretion. Levels of serum creatinine, creatinine clearance, and EDTA-GFR showed no significant change during treatment. Thirty-seven patients (42.8%) developed adverse events. Gastrointestinal intolerance in 25 (29%) and infections in 20 (23.2%) were the most frequent. The drug was discontinued in 14 (16.3%) patients due to side effects and 6 patients discontinued MMF because they achieved disease remission and were trying to conceive. MMF was stopped due to lack of efficacy in 12 patients.. Our data suggest that MMF is a good therapeutic alternative for patients with SLE and renal involvement or refractory disease activity.

Topics: Adult; Azathioprine; Cyclophosphamide; Female; Humans; Immunosuppressive Agents; Kidney; Lupus Nephritis; Male; Mycophenolic Acid; Proteinuria; Retrospective Studies; Severity of Illness Index; Survival Rate

Nephrotic syndrome (NS) is a clinical state characterized by massive proteinuria, hypoalbuminemia, and eventual edema formation. Although the mechanisms underlying this phenomenon are not yet fully clarified, it is well accepted that nephrin and podocin are involved in the development of proteinuria. The effects of early treatment with various antiproteinuric therapies on proteinuria and glomerular staining of nephrin and podocin in rats with experimental NS have not been previously studied. Proteinuria and glomerular nephrin and podocin immunofluorescence were examined in rat kidneys with adriamycin-induced NS and the effects of antiproteinuric drug therapies during 5 wk with enalapril, losartan, alone or in combination, omapatrilat, and mycophenolate mofetil on these parameters were assessed. Injection of adriamycin caused a significant increase in daily (from 21.8 +/- 1.4 to 983.1 +/- 45.8 mg/day, P < 0.01) and cumulative protein excretion (from negligible values to 22,490 +/- 931 mg, P < 0.001) during 5 wk. Early treatment with enalapril significantly decreased the daily (641.7 +/- 82.4 mg/day, P < 0.0023) and cumulative proteinuria (15,727 +/- 2,204 mg, P < 0.001). A similar effect, although to a lesser extent, was obtained after omapatrilat treatment: cumulative proteinuria was reduced to 18,706 +/- 1,042 mg, P < 0.001. In contrast, losartan treatment did not significantly influence the cumulative proteinuria that remained comparable (20,351 +/- 1,360 mg, P > 0.05) to that observed in untreated NS rats. Unexpectedly, when losartan was given in combination with enalapril, it abolished the beneficial effects of the latter. Pretreatment with mycophenolate mofetil exerted a moderate antiproteinuric effect, which appeared only during the last week of the experimental treatment. Nephrotic rats exhibited severe disruption of slit diaphragm structure as seen by rapid and profound loss of nephrin and podocin. Beneficial effects of enalapril, omapatrilat, and mycophenolate mofetil paralleled the preservation of nephrin, as determined immunohistochemically, and enabled prediction of significant antiproteinuric responses. Enalapril alone or in combination with losartan resulted in significant preservation of podocin. Pretreatment with enalapril, and to a lesser extent omapatrilat, is superior to losartan in reducing proteinuria in NS rats. A combination of ACE inhibitors with ANG II receptor blockers does not provide any advantageous antiproteinuric therapy in

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Doxorubicin; Enalaprilat; Enzyme Inhibitors; Fluorescent Antibody Technique; Immunohistochemistry; Intracellular Signaling Peptides and Proteins; Kidney Glomerulus; Losartan; Male; Membrane Proteins; Mycophenolic Acid; Nephrotic Syndrome; Protein Synthesis Inhibitors; Proteinuria; Pyridines; Rats; Rats, Sprague-Dawley; Thiazepines

Lupus membranous nephropathy (LMN) presents a difficult clinical problem as no particular treatment has been proven to be effective. Studies have shown good results with mycophenolate mofetil (MMF) in proliferative lupus nephropathy (LN) (WHO class III and IV disease).. To study whether MMF treatment was effective in membranous predominant LN in patients resistant to or intolerant of other immunosuppressive agents.. We retrospectively studied 10 patients with systemic lupus erythematosus who had biopsy-proven predominant LMN (six Vc patients and four Va or Vb patients). Previous treatments included cyclophosphamide, azathioprine, ciclosporin and corticosteroids. The following parameters were recorded at baseline and follow-up: blood pressure, ECLAM, proteinuria, serum albumin and creatinine, routine haematology and immunology.. The study included eight women and two men, mean age 38.4 +/- 7.1 yr (range 30-49 yr). The racial distribution was as follows: five Caucasian, and five Black patients. The mean treatment time with MMF was 18.8 +/- 15.4 months (range 3-52 months). Twenty-four-hour urinary protein excretion was reduced from median 2.26 g (range 0-7.92 g) to median 0.66 g (range 0.08-3.85 g) at follow-up (P = 0.0039). Serum albumin increased significantly after treatment from median 29.5 g/l (range 14.0-42.0 g/l) to 33.5 g/l (range 23.0-40.0 g/l) at follow-up (P = 0.04). There were no significant changes in serum creatinine (P = 0.55).. MMF is a potentially useful immunosuppressive agent in reducing the proteinuria associated with membranous predominant LN.

Topics: Adult; Female; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Lupus Nephritis; Male; Middle Aged; Mycophenolic Acid; Proteinuria; Retrospective Studies; Severity of Illness Index; Treatment Outcome

Sirolimus is a potent immunosuppressant, which may permit the avoidance of nephrotoxic calcineurin inhibitors (CNI). However, cases of proteinuria associated with sirolimus have been reported following renal transplantation. Here, we report three cases of proteinuria (1, 2 and 7 g/day) developing during therapy with sirolimus plus low-dose tacrolimus following clinical islet transplantation (CIT) in type I diabetic subjects. The proteinuria resolved after discontinuation of sirolimus, substituted by mycophenolate mofetil (MMF) combined with an increased dose of tacrolimus. A renal biopsy in one case indicated only the presence of diabetic glomerulopathy. Five other CIT recipients developed microalbuminuria while on sirolimus which all resolved after switching to tacrolimus and MMF. The resolution of proteinuria from the native kidneys of CIT recipients after the discontinuation sirolimus suggests that, at least in some individuals, sirolimus itself may have adverse renal effects. Sirolimus should be used cautiously with close monitoring for proteinuria or renal dysfunction.

Topics: Adult; Albuminuria; Diabetes Mellitus, Type 1; Female; Glomerulonephritis; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Islets of Langerhans Transplantation; Kidney; Kidney Transplantation; Living Donors; Middle Aged; Mycophenolic Acid; Proteinuria; Sirolimus; Tacrolimus; Time Factors; Treatment Outcome

Mesangial IgA glomerulonephritis (MIgAGn) is the most common biopsied primary glomerulonephritis worldwide, with a poor long-term prognosis for renal function in over a third of all patients. No proven therapy currently exists for MIgAGn. Recent studies have suggested some benefit with mycophenolate mofetil (MMF), especially in hypertensive patients with kidney failure and proteinuria, though other studies have failed to corroborate these findings. We report eight adult patients with biopsy proven MIgAGn followed in a single hospital. They all received angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers. Compassionate use of MMF was based on the presence of clinical and analytical data suggesting a high risk of short- to medium-term progression to chronic renal failure. MMF treatment was stopped after two and three months in two patients who had advanced renal failure at the start of therapy because of disease progression and greater fluid retention. Several months later they both required dialysis and kidney transplantation. The mean duration of MMF therapy in the other six patients was 15 (range: 10-18) months. The mean serum creatinine concentration fell from 1.82 +/- 0.47 to 1.55 +/- 0.41 mg/dl (p = 0.04). Protein loss in 24-hour urine collection fell from 1.95 +/- 1.35 to 0.77 +/- 0.58 g/day (p = 0.02). These results in this low number of patients showed that treatment with MMF in high-riks patients with MIgAGn and early stage kidney failure generally stabilized the disease and reduced proteinuria. MMF was well tolerated and may be of some benefit in a subgroup of patients with MIgAGn and a poor prognosis.

Topics: Adult; Creatinine; Data Interpretation, Statistical; Disease Progression; Female; Follow-Up Studies; Glomerulonephritis, IGA; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prognosis; Prospective Studies; Proteinuria; Renal Dialysis; Risk Factors; Time Factors; Treatment Outcome

We examined our renal transplant population for glomerular diseases demonstrated on biopsy between January 1993 and April 2002, focusing on transplant glomerulopathy (TGP). Of 1156 patients followed in our clinics during this period, glomerular disease was diagnosed in 132 cases (11.4%). Glomerulonephritis was diagnosed in 86 transplants (7.4%), with IgA nephropathy (IgAN) being the commonest diagnosis [32 cases (2.8%)]. Thirty-one cases (2.7%) of biopsy-proven TGP were analyzed for associated factors compared with 27 cases (2.3%) of recurrent IgAN. Transplant glomerulopathy was less frequent with mycophenolate mofetil (MMF) and/or tacrolimus, whereas recurrent IgAN showed no such tendency (P= 0.02). Peritubular capillary (PTC) C4d deposition was observed in six of 24 cases (25%) with TGP but none with recurrent IgAN (P= 0.02). Peritubular capillary basement membrane (BM) multilayering was significantly greater in TGP (4.92 +/- 2.94) than in recurrent IgAN (1.86 +/- 1.04) (P < 0.001). The graft survival of TGP was worse than recurrent IgAN (P= 0.05). The association of TGP with BM multilayering and C4d deposits in PTC suggests a generalized disorder of the graft microcirculation and its BM, owing to antibody-mediated rejection in at least some cases. Transplant glomerulopathy has a serious prognosis but is less frequent in patients on newer immunosuppression, unlike recurrent IgAN.

Topics: Age Factors; Basement Membrane; Biopsy; Capillaries; Complement C4b; Female; Graft Survival; Humans; Immunoglobulin A; Immunosuppressive Agents; Kidney; Kidney Glomerulus; Kidney Transplantation; Male; Mycophenolic Acid; Nephrons; Peptide Fragments; Proteinuria; Tacrolimus; Time Factors

In this Grand Round we present a 32-yr-old African man who became severely ill after a 5-month history of weight loss, pyrexia, arthralgia, sweats and rash. He went on to develop pericarditis, pericardial effusion with tamponade, hepatomegaly with abnormal liver function tests, lymphadenopathy, massive proteinuria and required ventilatory, circulatory and renal support. The differential diagnosis was adult onset Still's disease, systemic lupus erythematosus (SLE), infection and lymphoma. Primary infection and lymphoma were excluded and he was treated, with dramatic success, with intravenous immunoglobulins (i.v.IG). Subsequent renal biopsy excluded SLE but confirmed collapsing glomerulopathy. The proteinuria improved dramatically following treatment with mycophenolate mofetil. We discuss some of the difficult diagnostic and management issues raised by this patient and the different uses and mechanisms of action of i.v.IG.

Topics: Acute Kidney Injury; Adult; Combined Modality Therapy; Diagnosis, Differential; Follow-Up Studies; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Male; Mycophenolic Acid; Proteinuria; Still's Disease, Adult-Onset

We studied the effects of mycophenolate mofetil, a specific inhibitor of inosine monophosphate dehydrogenase, on the mercuric chloride induced autoimmune glomerulonephritis in Brown Norway rats and also on the renal contents of adrenomedullin. In the rats with autoimmune glomerulonephritis, plasma and renal tissue adrenomedullin levels were increased significantly. Coadministration of mycophenolate mofetil resulted in prevention of autoimmune glomerulonephritis and also in maintaining of plasma and renal tissue adrenomedullin levels at control levels. Adrenomedullin mRNA expressions in the renal cortex were also higher in the rats with autoimmune glomerulonephritis. Significant positive correlations were found between renal cortical adrenomedullin levels and urinary Na+ and N-acetyl-beta-D-glucosaminidase excretion. A significant negative correlation between renal cortical adrenomedullin levels and creatinine clearance was also found. These results suggest that mycophenolate mofetil suppresses the renal damage in rats with autoimmune glomerulonephritis and renal adrenomedullin may participate in the pathophysiology of autoimmune glomerulonephritis.

Topics: Adrenomedullin; Animals; Blotting, Northern; Glomerulonephritis, Membranoproliferative; Immunosuppressive Agents; IMP Dehydrogenase; Kidney; Male; Mercuric Chloride; Mycophenolic Acid; Peptides; Proteinuria; Purines; Radioimmunoassay; Rats; Rats, Inbred BN

Glomerular crescent formation is a prominent feature of aggressive forms of glomerulonephritis (GN) and is associated with a poor prognosis. We investigated whether the potent immunosuppressive agent mycophenolate mofetil (MMF) could prevent crescent formation in a model of anti-glomerular basement membrane (GBM) GN in the rat.. GN with glomerular crescents was induced by the injection of anti-GBM antibody to female Wistar-Kyoto (WKY/NCrj) rats. The experimental rats were divided into two groups: rats received vehicle (0.5% carboxymethylcerlose) or MMF (20 mg/kg/day) orally. Body weight was measured and the urine and blood samples were evaluated. The rats were sacrificed at day 14, and histological analysis was performed. The mRNA expression of cytokines and adhesion molecules in the kidney was analysed by reverse transcription-polymerase chain reaction (RT-PCR).. Marked proteinuria, glomerular crescent formation and glomerulosclerosis were observed in this model, and these were significantly reduced by MMF treatment. Marked glomerular macrophage and T-cell infiltration was also observed, and MMF treatment significantly inhibited macrophage but not T-cell infiltration. RT-PCR and immunohistochemical analysis revealed that mRNA and protein expression of osteopontin was decreased by the treatment with MMF. In addition, MMF treatment in the early stages of GN could inhibit proteinuria, glomerular crescent formation and glomerulosclerosis.. These findings suggest therapeutic potential for MMF in the inhibition of glomerular crescent formation in GN and provide new insights into the mechanism underlying the amelioration of crescentic GN by MMF treatment.

Topics: Animals; Anti-Glomerular Basement Membrane Disease; Female; Immunosuppressive Agents; Kidney Glomerulus; Macrophages; Mycophenolic Acid; Osteopontin; Proteinuria; Rats; Rats, Inbred WKY; Sialoglycoproteins; T-Lymphocytes

Treatment of adults with idiopathic membranoproliferative glomerulonephritis (IMPGN) is often unrewarding with approximately 60% of patients progressing to end-stage renal failure within 10 years. Although children with IMPGN may respond to steroid therapy, there is no significant benefit to treating adult IMPGN patients with immunosuppression.. Outcome measures in five patients with IMPGN who were treated with oral prednisolone and mycophenolate mofetil (MMF) (treatment group) were compared with six patients with IMPGN who did not receive immunosuppression (control group).. There was no significant difference between either group in baseline clinical characteristics or systolic and diastolic blood pressure during observation. In the treatment group, there was a significant reduction in proteinuria from a baseline of 5.09 to 1.97 g/24 h (P = 0.003) at 6 months, 1.96 g/24 h (P = 0.003) at 12 months and 2.59 g/24 h (P = 0.015) at 18 months. There was no significant change in proteinuria over 18 months in the control group. Serum creatinine concentration and creatinine clearance did not change significantly over 18 months in the treatment group. In the control group, there were significant changes in serum creatinine and creatinine clearance over 18 months [baseline 103 to 159 micromol/l (P = 0.004) and baseline 108 to 67 ml/min (P > 0.001), respectively] when compared to baseline, although the differences were not significant when the two groups were compared directly.. This preliminary study suggests that in the short term, the combination of MMF and prednisolone can significantly reduce proteinuria and may preserve renal function in patients with IMPGN.

Topics: Adrenal Cortex Hormones; Adult; Creatinine; Female; Follow-Up Studies; Glomerulonephritis, Membranoproliferative; Humans; Immunosuppressive Agents; Male; Mycophenolic Acid; Proteinuria; Retrospective Studies; Serum Albumin; Time Factors; Treatment Outcome

Chronic allograft nephropathy (CAN) is the most common cause of late graft loss. A beneficial effect of mycophenolate mofetil (MMF) on CAN was observed, although, due to the loss of body weight (BW) under MMF, serum creatinine (sCr) and reciprocal sCr may be unsuitable markers of graft function.. In 17 kidney transplant patients with CAN, azathioprine (Aza) was replaced by MMF. The remaining therapy was not changed; specifically, the cyclosporine (CsA) dose was not decreased. The mean values and regression coefficients of reciprocal sCr, CCr, urinary creatinine excretion (uCr x V), proteinuria, BW, blood pressure (BP), serum cholesterol (sChol), and serum triglycerides (sTG) versus time were analyzed 12 months before and after institution of MMF by a paired-comparison t test.. The mean regression coefficient of reciprocal sCr differed significantly before and after conversion to MMF (mean -0.01 +/- 0.01 vs +0.012 +/- 0.029 mg/dL per month), suggesting improved graft function. However, the mean values of BW (74 +/- 15 vs 71 +/- 15 kg, P <.001) and uCr x V (1152 +/- 321 vs 1065 +/- 266 mg per 24 hours, P=.0897) decreased, making the increase in CCr less significant (mean -1.16 +/- 2.69 vs 0.40 +/- 1.79 mL/min per month, P <.05). BP, sChol, sTG, and proteinuria before and after conversion did not differ significantly. Among patients with long-term stable graft function at 36.5 +/- 16.9 months after conversion to MMF there was an almost significant improvement in renal protein excretion.. MMF improved graft function, although this effect was overestimated using reciprocal sCr. Other risk factors, such as BP, sChol, and sTG, showed no significant differences, suggesting that MMF accounted for the improvement in CAN. The course of proteinuria under MMF seems to be of prognostic significance.

Topics: Albuminuria; Azathioprine; Body Weight; Creatinine; Cyclosporine; Drug Therapy, Combination; Graft Survival; Humans; Immunosuppressive Agents; Isoantigens; Kidney Transplantation; Mycophenolic Acid; Postoperative Complications; Proteinuria

Although renal protective effect of interrupting the inflammatory process is well established, it is still controversial if it also prevents the glomerular hemodynamic disturbances that initiate renal injury. We investigated the effects of suppressing inflammation with mycophenolate mofetil (MMF) on glomerular hemodynamics, arteriolar structural changes, and renal histologic injury in rats with subtotal renal ablation. Micropuncture studies were performed 30 days after 5/6 nephrectomy in rats untreated and treated with MMF (30 mg/kg/day). Renal histology, immunohistochemistry for lymphocytes, macrophages and inducible nitric oxide synthase (iNOS) expression, as well as afferent arteriolar (AA) morphometry was evaluated.. Renal ablation significantly increased proteinuria (6.8 to 82.7 mg/day), mean arterial pressure (MAP) (120 to 166 mm Hg), single-nephron glomerular filtration rate (SNGFR) (34.8 to 56.3 nL/min), glomerular plasma flow (QA) (117.7 to 246.9 nL/min), and glomerular capillary pressure (PGC) (48.9 to 61.0 mm Hg). Afferent resistance (AR), efferent resistance, and ultrafiltration coefficient remained unchanged. Despite persisting arterial hypertension (152 mm Hg), MMF prevented proteinuria (13.3 mg/day), and significantly reduced SNGFR (44.4 nL/min), PGC (49.1 mm Hg), and QA (163.2 nL/min) due to a rise in AR (3.13 vs. 2.18 1010 dyn/sec/cm-5). Glomerular sclerosis, tubulointerstitial damage, lymphocyte and macrophage infiltration, and iNOS expression were significantly reduced by MMF, in addition hypertrophy of AA resistance evaluated by the media/lumen ratio was prevented (P < 0.001).. Reduction in proteinuria, SNGFR, QA, and PGC, despite elevated MAP, indicate preservation of AA function. These results suggest that inflammation associated arteriolopathy of AA contributes to glomerular hemodynamic disturbances that participate in the progression of renal disease.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arterioles; Hypertension, Renal; Kidney; Male; Mycophenolic Acid; Nephrectomy; Nephritis; Proteinuria; Rats; Rats, Sprague-Dawley; Renal Circulation

Topics: Female; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Proteinuria; Treatment Outcome

Topics: Animals; Autoimmune Diseases; Immunosuppressive Agents; Mycophenolic Acid; Nephritis; Proteinuria; Rats

Mycophenolate mofetil (MMF), an immunosuppressive drug commonly used in organ transplantation, is increasingly being used to treat autoimmune diseases including systemic lupus erythematosus (SLE). Excessive production of nitric oxide (NO) by inducible nitric oxide synthase (iNOS) has been implicated in the pathogenesis of lupus nephritis. We evaluated the effect of MMF on the severity of nephritis and the production of NO in lupus-prone MRL/lpr mice. Eight-week-old female MRL/lpr mice (n = 20) were treated with MMF (100 mg/kg/day) by oral gavage for 12 weeks. Control mice (n = 20) received vehicle on the same schedule. The mice were killed after 12 weeks of treatment. Treatment with MMF significantly decreased the amount of proteinuria, prolonged survival and reduced the histological severity of glomerulonephritis. Urinary nitrite/nitrate excretion in the MMF-treated mice was significantly reduced during the first 8 weeks of treatment. However, by the end of the 12 weeks' treatment period, there was no significant difference between vehicle and MMF-treated mice in terms of urinary nitrite/nitrate excretion, intra-renal production of NO, expression of iNOS protein and induction of iNOS mRNA. We conclude that MMF is effective in attenuating the severity of nephritis in MRL/lpr mice. The beneficial effects of MMF on lupus nephritis during the early phase of the disease might be partly attributed to the inhibition of NO production. The inhibitory effect of MMF on NO production diminishes as the disease progresses. MMF probably has additional, as yet undefined mode of actions to fully account for its beneficial effects on lupus nephritis.

Topics: Animals; Female; Gene Expression Regulation, Enzymologic; Immunosuppressive Agents; Kidney; Lupus Nephritis; Mice; Mice, Inbred MRL lpr; Mycophenolic Acid; Nitrates; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitrites; Proteinuria; RNA, Messenger; Severity of Illness Index; Survival Rate

Recent evidence suggests that salt-sensitive hypertension develops as a consequence of renal infiltration with immunocompetent cells. We investigated whether proteinuria, which is known to induce interstitial nephritis, causes salt-sensitive hypertension. Female Lewis rats received 2 g of BSA intraperitoneally daily for 2 wk. After protein overload (PO), 6 wk of a high-salt diet induced hypertension [systolic blood pressure (SBP) = 156 +/- 11.8 mmHg], whereas rats that remained on a normal-salt diet and control rats (without PO) on a high-salt diet were normotensive. Administration of mycophenolate mofetil (20 mg. kg(-1). day(-1)) during PO resulted in prevention of proteinuria-related interstitial nephritis, reduction of renal angiotensin II-positive cells and oxidative stress (superoxide-positive cells and renal malondialdehyde content), and resistance to the hypertensive effect of the high-salt diet (SBP = 129 +/- 12.2 mmHg). The present studies support the participation of renal inflammatory infiltrate in the pathogenesis of salt-sensitive hypertension and provide a direct link between two risk factors of progressive renal damage: proteinuria and hypertension.

Topics: Animals; Body Weight; Dietary Proteins; Female; Hypertension, Renal; Immunosuppressive Agents; Kidney Glomerulus; Lymphocytes; Mycophenolic Acid; Nephritis, Interstitial; Oxidative Stress; Proteinuria; Rats; Rats, Inbred Lew; Sodium Chloride, Dietary

Mycophenolate mofetil (MMF) is a new immunosuppressive drug whose active metabolite, mycophenolic acid (MPA), blocks the action of inosine monophosphate dehydrogenase, resulting in the inhibition of the novo purine synthesis. Thus, MPA has an antiproliferative effect on T and B lymphocytes and also inhibits the glycosylation of cell surface adhesion proteins involved in cell-cell contact and in the recruitment of circulating leukocytes to sites of tissue damage and inflammation. In this study, the effect of MMF in the mercury model of nephritis was examined. Repeated exposure to HgCl(2) induces an autoreactive Th2 cell subset-inducing polyclonal B cell activation in the Brown Norway (BN) rat. This leads to the development of an autoimmune syndrome characterized by synthesis of autoantibodies (mainly anti-glomerular basement membrane [GBM] Abs) with glomerular linear deposits of IgG, proteinuria, and tubulointerstitial nephritis. Results show that MMF has a preventive effect on mercury-induced disease as it blocks anti-GBM Ab synthesis, thus avoiding glomerular IgG deposits and proteinuria and the development of interstitial nephritis. However, the therapeutic effect of MMF seems to be restricted to its antiinflammatory properties blocking the extravasation of circulating leukocytes to renal interstitium by interfering with the very late activation antigen 4/vascular cell adhesion molecule-1 (VCAM-1) cell adhesion pathway. Also, MMF administration to mercury-injected rats reduces the secretion of the proinflammatory cytokine tumor necrosis factor-alpha. These findings confirm that MMF has a strong effect on the primary immune response in this model. Nevertheless, when the disease is in progress, MMF acts exclusively on the inflammatory response. MMF could be useful in the treatment of diseases associated with renal inflammation.

Topics: Animals; Antibodies; Antibody Formation; Autoantibodies; Autoimmune Diseases; Female; Immunosuppressive Agents; Integrin alpha4beta1; Integrins; Kidney; Kidney Glomerulus; Kinetics; Mercuric Chloride; Mycophenolic Acid; Nephritis; Proteinuria; Rats; Rats, Inbred BN; Receptors, Lymphocyte Homing; Tumor Necrosis Factor-alpha

Topics: Biopsy; Blood Pressure; Creatinine; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Kidney Function Tests; Kidney Transplantation; Male; Mycophenolic Acid; Proteinuria; Retrospective Studies; Time Factors; Transplantation, Homologous

Overexpression of inducible nitric oxide synthase (iNOS) has been implicated in the pathogenesis of lupus glomerulonephritis. Mycophenolate mofetil (MMF), a novel immunosuppressive agent, is currently used in organ transplantation and under evaluation for treatment of autoimmune disorders. Mycophenolic acid, the active metabolite of MMF, has been shown to suppress cytokine-induced nitric oxide production in vitro. The aim of this study was to evaluate the effect of MMF on the expression of renal cortical iNOS mRNA and protection against glomerulonephritis in MRL/lpr mice. Three-month-old MRL/lpr mice (n = 6) displaying clinical symptoms of glomerulonephritis were treated for 3 months with MMF (90 mg/kg/day) dissolved in a vehicle. Controls were age- and sex-matched mice (n = 6) that received the vehicle alone. By reverse-transcription competitive polymerase chain reaction, we found that the renal cortical iNOS/beta-actin mRNA ratio was reduced by 30.8% (P <.05) in MMF-treated mice. Furthermore, MMF significantly reduced urinary nitrite production and degree of glomerulosclerosis. The glomerular volume was reduced by 17.5% (P <.001). Proteinuria was also significantly reduced in the MMF-treated group. However, by electrophoretic mobility shift assay, the nuclear binding of nuclear factor-kappaB (NF-kappaB) was not affected by MMF treatment. We conclude that in addition to its immunosuppressive action, MMF may reduce renal cortical iNOS mRNA expression and diminish glomerulosclerosis in MRL/lpr mice independent of modulation of the NF-kappaB pathway.

Topics: Animals; Cell Count; Creatinine; Enzyme Inhibitors; Female; Gene Expression Regulation, Enzymologic; Glomerulosclerosis, Focal Segmental; Immunohistochemistry; Kidney Glomerulus; Lupus Nephritis; Mice; Mice, Inbred MRL lpr; Mycophenolic Acid; NF-kappa B; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Proteinuria; RNA, Messenger; Transcriptional Activation

Approaches to the treatment of lupus nephritis include immunosuppressants associated with anti-inflammatory drugs, mainly steroids, which, however, cause major side effects. Mycophenolate mofetil (MMF) has been described as being less toxic than conventional immunosuppressants, and it was effective in preventing progressive nephritis in lupus mice. Our study evaluated the therapeutic effect of MMF in NZB/W F1 hybrid mice with established disease. We also examined the combination of MMF with a selective cyclooxygenase-2 (COX-2) inhibitor, DFU, based on previous findings of excessive renal production of COX-2-derived thromboxane A2 (TXA2) in lupus nephritis.. Four groups of NZB/W mice (N = 30 each group), starting at five months of age, were given daily by gavage the following: vehicle, MMF 60 mg/kg, DFU 3 mg/kg, or MMF + DFU. Fifteen mice for each group were used for the survival studies, and the remaining mice were sacrificed at nine months.. MMF or DFU alone partially delayed the onset of proteinuria compared with vehicle. Combined therapy was significantly (P < 0.05) more effective than single drugs. Animal survival was partially ameliorated by MMF and significantly improved by the drug combination in comparison with the vehicle (P = 0.005) and DFU alone (P < 0.03). At nine months, serum blood urea nitrogen (BUN) levels were lower in all of the treated groups than in the vehicle group. Renal damage was also limited, but to a greater extent in mice given the combined therapy. In untreated mice, renal COX-2 mRNA expression was up-regulated, and generation of TXB(2), the stable breakdown product of TXA(2), increased. DFU prevented the abnormal renal TXB(2) production, confirming the COX-2 origin of this eicosanoid, whereas renal 6-keto-PGF(1 alpha) and prostaglandin E(2) (PGE(2)) were not affected substantially.. These results offer a strong case for exploring the possibility that in humans MMF combined with COX-2 inhibitors has a role in the treatment options for lupus nephritis. This combined drug therapy may be at least as effective as steroids but without the obvious nephrotoxicity of the latter.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Antibodies, Antinuclear; Blood Urea Nitrogen; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Disease Models, Animal; Drug Therapy, Combination; Female; Furans; Gene Expression Regulation, Enzymologic; Immunosuppressive Agents; Isoenzymes; Kidney; Lupus Nephritis; Lymphocyte Count; Lymphocyte Subsets; Membrane Proteins; Mice; Mice, Inbred NZB; Mycophenolic Acid; Prostaglandin-Endoperoxide Synthases; Proteinuria; Spleen; Survival Rate; Thromboxane B2

Antigen-dependent and antigen-independent factors have been implicated in the pathophysiology of chronic allograft rejection, but their relative role is not well established. In the Fisher 344-->Lewis rat kidney transplant model, we sought (1) to compare the relative efficacy of the novel immunosuppressant, mycophenolate mofetil (MMF), with that of the AT1 receptor blocker, losartan, in preventing the development of chronic graft rejection when given for 52 wk; (2) to examine whether combining MMF with losartan affords better protection than each of the drugs alone. For comparison, the effect of cyclosporine (CsA) to control chronic graft rejection was also assessed. Administration of MMF alone or losartan alone to the kidney allografted rats resulted in a partial decrease in the amount of proteinuria, preservation of glomerular and tubulo-interstitial graft structure, limitation of intragraft cell infiltration, and improvement of graft survival compared with corresponding parameters in untreated, transplanted control rats. Combined treatment with MMF and losartan completely prevented the development of proteinuria, largely reduced glomerular and tubulointerstitial injury, and suppressed intragraft cell infiltration, and all animals survived at the end of the follow-up. Similarly, CsA treatment largely prevented graft injury but failed to achieve 100% animal survival. We have shown that MMF synergizes with the angiotensin II receptor antagonist, losartan, in simultaneously targeting complementary pathways of chronic allograft rejection. Combining MMF and angiotensin II receptor blocker offers superior long-term renoprotection as compared with CsA. Together, these findings provide the basis to prevent chronic injury and progressive dysfunction after renal transplantation.

Topics: Angiotensin Receptor Antagonists; Animals; Blood Pressure; Chronic Disease; Creatinine; Cyclosporine; Drug Therapy, Combination; Graft Rejection; Graft Survival; Hemodynamics; Immunohistochemistry; Immunosuppressive Agents; Kidney; Kidney Transplantation; Losartan; Mycophenolic Acid; Proteinuria; Rats; Rats, Inbred F344; Rats, Inbred Lew; Receptor, Angiotensin, Type 1; Renal Circulation; Transplantation, Homologous; Transplantation, Isogeneic

Myofibroblasts have been shown to play a pivotal role in the synthesis of extracellular matrix components in several animal models of renal fibrosis. The purpose of the present study was to investigate whether mycophenolate mofetil (MMF) reduces interstitial myofibroblast infiltration and collagen III deposition in 5/6 nephrectomized rats.. Forty-five Wistar rats underwent 5/6 renal ablation and received by daily oral gavage either vehicle (N = 20) or MMF (N = 25) during the 60 days following surgery. Groups of five treated and five untreated rats were killed at two, four, and eight weeks after subtotal nephrectomy. Four untreated and three treated rats were killed at week 12, one month after treatment withdrawal. At the time of sacrifice, proteinuria, plasma, and urine creatinine were determined. Immunohistochemistry was performed on renal tissue for alpha-smooth muscle actin (alpha-SMA), a cytoskeletal marker of myofibroblasts, for type III collagen, and for proliferating cell nuclear antigen (PCNA). Moreover, in order to study the in vitro effects of MMF on fibroblast proliferation, rat fibroblasts were cultured in the presence or absence of mycophenolic acid (MPA).. At all periods studied, MMF treatment improved renal functional parameters and progressively decreased remnant kidney hypertrophy and glomerular volume increment. Proliferating cells in renal tubules, interstitium, and glomeruli, as well as interstitial myofibroblast infiltration and interstitial type III collagen deposition, were also significantly reduced by MMF treatment. In addition, MPA exhibited a dose-dependent inhibitory effect on in vitro proliferation of rat fibroblasts.. Reduction of interstitial myofibroblast infiltration may be an important event by which MMF significantly prevents renal injury following subtotal renal ablation. Thus, our results suggest that MMF could be useful to limit the progression of chronic renal disease toward end-stage renal failure.

Topics: Actins; Animals; Cell Division; Cells, Cultured; Collagen; Creatinine; Dose-Response Relationship, Drug; Enzyme Inhibitors; Extracellular Matrix; Fibroblasts; Fibrosis; Kidney; Kidney Failure, Chronic; Mycophenolic Acid; Nephrectomy; Proliferating Cell Nuclear Antigen; Proteinuria; Rats; Rats, Wistar; Regeneration; Weight Loss

Extensive renal ablation is associated with progressive sclerosis of the remnant kidney. Because lymphocytes and monocytes accumulate in the remnant kidney, it is likely that they play a role in the renal scarring. Therefore, we treated rats with 5/6 nephrectomy (5/6Nx) with mycophenolate mofetil (MMF), a drug that has an antiproliferative effect and that suppresses the expression of intercellular adhesion molecules.. Sprague-Dawley rats with 5/6Nx received MMF (30 mg. kg-1. day-1 by daily gastric gavage, N = 15) or vehicle (N = 16). Ten additional rats were sham operated. All rats were fed a 30% protein diet. Body weight, serum creatinine, and urinary protein excretion were determined weekly. Lipid peroxidation, as a measure of oxidative stress observed by urinary malondialdehyde determinations, was performed every two weeks. Histologic studies were done in the remnant kidney four weeks (9 rats from the vehicle-treated group, 7 rats from the MMF group, and 5 sham-operated rats) and eight weeks after surgery (the remaining rats). Glomerular volume, sclerosis in glomeruli (segmental and global) and interstitium (semiquantitative scale), infiltrating lymphocytes and macrophages (CD43- and ED1-positive cells), and expression of adhesion molecules (CD54, CD18, and CD11b) were analyzed.. MMF treatment prevented the progressive increment in serum creatinine and the proteinuria observed in the 5/6 nephrectomized rats during the eight weeks of observation (P < 0.01). Weight gain was comparable in the MMF-treated and sham-operated rats, whereas weight gain was decreased in untreated 5/6 nephrectomized rats. Excretion of malondialdehyde increased after surgery but returned sooner to control levels in the MMF-treated rats. Increments in glomerular size and mean arterial blood pressure induced by renal ablation were not modified by MMF treatment. Eight weeks after surgery, segmental sclerosis was present in 48.4 +/- 8.35% (+/- sd) glomeruli in the vehicle-treated group versus 25 +/- 10.5% in the MMF-treated group (P < 0.001). Interstitial fibrosis was reduced significantly with MMF treatment (P < 0.001). Infiltration with CD43- and ED1-positive cells in glomeruli and interstitium was two to five times lower in MMF-treated rats (P < 0.01). Expression of adhesion molecules CD18 and CD11b was similarly reduced.. MMF ameliorates the progressive renal damage in the remnant kidney after 5/6Nx. This effect is associated with a reduction in the infiltration of lymphocytes and monocytes, whereas glomerular hypertrophy and systemic hypertension are unchanged.

Topics: Animals; Blood Pressure; Cell Adhesion Molecules; Creatinine; Disease Models, Animal; Hypertension, Renal; Hypertrophy; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Glomerulus; Lymphocytes; Male; Monocytes; Mycophenolic Acid; Nephrectomy; Proteinuria; Rats; Rats, Sprague-Dawley

Chronic renal diseases progress to organ insufficiency, which may require replacement therapy within one to three decades even independently of the type of initial insults. In the majority of cases, the degrees of proteinuria and interstitial leukocyte infiltration and scarring are strictly correlated with the rate of disease progression. This study tests the hypothesis that excess intrarenal protein traffic may cause lymphocyte-dependent interstitial injury that, while not fully controlled by antiproteinuric therapy, can be further inhibited by concomitant immunosuppression. A primarily nonimmune model was used to reproduce progressive renal disease due to a critical loss of nephron mass. Angiotensin-converting enzyme (ACE) inhibitor limited proteinuria, interstitial inflammation, MHC class II antigen expression, and severe lesions. Combined treatment with ACE inhibitor and a specific antilymphocyte agent, mycophenolate mofetil, dramatically attenuated macrophage and T cell infiltration, MHC-class II overexpression, dendritic cells, and all manifestations of the disease. Evidence of lymphocyte-mediated renal injury in the setting of excess protein traffic provides the basis for combining ACE inhibition and immunosuppression to halt progression of proteinuric kidney disease and minimize the need for dialysis or transplantation.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Disease Models, Animal; Immunosuppressive Agents; Kidney; Kidney Failure, Chronic; Lisinopril; Lymphocytes; Male; Mycophenolic Acid; Proteinuria; Rats; Rats, Sprague-Dawley

Topics: Adult; Creatinine; Cyclosporine; Female; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prednisone; Proteinuria; Renal Dialysis; Reoperation; Risk Factors

Mycophenolate mofetil (MMF) represents a powerful immunosuppressant in organ transplantation. The aim of this study was to determine the anti-inflammatory effects of MMF on mesangial cells. Cultured rat mesangial cells were exposed to mycophenolic acid (MPA) in concentrations of 0.1 to 10 microM. MPA inhibited the proliferation of these cells in a dose-dependent manner. A maximum of 98% inhibition was obtained by a 2-d exposure of mesangial cells to > or =5 microM MPA. As expected, the addition of > or =75 microM guanosine prevented the antiproliferative effect of MPA completely. Subsequently, in vivo studies were performed in the anti-Thy1.1 nephritis model. Sixty-six male Wistar rats were investigated: healthy rats (n = 15), treated healthy rats (n = 6), nephritic rats (n = 15), and treated nephritic rats (n = 30). MMF therapy (40 mg/kg body wt per d) of nephritic animals was initiated 2 d before (n = 3) and 6 h (n = 15) or 2 d (n = 12) after induction of nephritis. Renal histology was analyzed at days +6 and +9 after initiation of disease. Therapy of nephritic rats by MMF resulted in a significant amelioration of glomerular histology, assessed by glomerular cellularity, synthesis of alpha-smooth muscle actin, extracellular matrix deposition, and glomerular hypertrophy. Proteinuria, expressed as areas under the curve of protein/creatinine ratios versus time, showed a clear tendency toward a reduction by MMF therapy. Healthy control rats were not negatively affected by exposure to MMF. In summary, this study shows that mesangial cell proliferation can be significantly inhibited by MPA in vitro and in vivo. MMF represents a new approach to the therapy of experimental mesangial cell-mediated forms of glomerulonephritis.

Topics: Animals; Cells, Cultured; Enzyme Inhibitors; Extracellular Matrix Proteins; Fluorescent Antibody Technique; Glomerular Mesangium; Glomerulonephritis; Immunosuppressive Agents; Isoantibodies; Male; Mycophenolic Acid; Proteinuria; Rats; Rats, Wistar

The effect of mycophenolate mofetil (MMF) was examined in active Heymann nephritis (HN), an animal model of human membranous nephropathy. HN was induced in Lewis rats with Fx1A/complete Freund's adjuvant (CFA), and controls only received CFA. The induction of HN was prevented by MMF (30 mg/kg per d) from 0 to 4 wk after immunization. Proteinuria was not different in CFA controls up to 16 wk, and was significantly less than in untreated HN from 6 wk onward. Serum anti-Fx1A antibody (Ab) levels and glomerular Ig deposition were suppressed during therapy. The interstitial infiltrate of alphabetaTCR+, CD4+ and CD8+ T cells, natural killer cells, and macrophages (mphi) observed in untreated HN at 8 wk was absent from rats treated from 0 to 4 wk with MMF. Semiquantitative reverse transcription-PCR for renal mononuclear cell cytokine mRNA at 8 wk demonstrated that MMF from 0 to 4 wk prevented the increased expression of Th1 (interferon-gamma, lymphotoxin), Th2 (interleukin-4), and mphi (tumor necrosis factor-alpha) cytokines identified in untreated HN. In lymph node draining sites of immunization, MMF limited both enlargement and the increased proportion of CD3+, CD4+, and CD8+ T cells observed in untreated HN and CFA controls. MMF suppressed Th2 (interleukin-4) but not Th1 (interferon-gamma, lymphotoxin) cytokine mRNA expression in lymph nodes. MMF from 4 to 8, 6 to 12, or 10 to 14 wk did not prevent proteinuria, serum anti-Fx1A Ab, or glomerular IgG deposition when compared with untreated HN. This study showed that MMF from 0 to 4 wk prevented the induction of HN and was associated with preferential suppression of Th2 cytokines. This therapy may prove useful in human idiopathic membranous nephropathy.

Topics: Animals; Disease Models, Animal; Drug Evaluation, Preclinical; Glomerulonephritis; Glomerulonephritis, Membranous; Humans; Interferon-gamma; Interleukins; Kidney Cortex; Lymphokines; Male; Mycophenolic Acid; Proteinuria; Rats; Rats, Inbred Lew; RNA, Messenger; Th1 Cells; Th2 Cells; Tumor Necrosis Factor-alpha

Classical immunosuppressants like cyclophosphamide give excellent results in human lupus nephritis. However, they augment malignancies and viral infections. Here we investigated the effect of the new immunosuppressant agent, mycophenolate mofetil (MMF), in New Zealand Black x New Zealand White (NZBxW) F1 hybrid mice, a model of genetically determined immune complex disease that mimics systemic lupus in humans. MMF has a selective antiproliferative effect on T- and B-lymphocytes, inhibits antibody formation and blocks the glycosylation of lymphocyte glycoproteins involved in the adhesion of leukocytes to endothelial cells. Two groups of NZBxW mice were used: group 1 (N = 20) given daily MMF (60 mg/kg p.o.) and group 2 (N = 15) given daily vehicle alone. Treatment started at three months of age and lasted until the death of the animals. Results showed that percentage of proteinuric mice was significantly reduced by MMF treatment and serum BUN levels were also lower than vehicle. MMF had a suppressive effect on autoantibody production and protected animals from leukopenia and anemia. Life survival of MMF treated lupus mice was significantly improved in respect to untreated animals. Thus, MMF delayed renal function deterioration and prolonged life survival in murine lupus nephritis. MMF has been already recognized as reasonably well tolerated in renal transplant patients and despite its gastrointestinal toxicity its overall safety profile appears superior to azathioprine. Human studies are needed to establish whether MMF may function as a steroid-sparing drug in lupus nephritis.

Topics: Animals; Antibodies, Antinuclear; Body Weight; DNA; Female; Immunosuppressive Agents; Kidney; Lupus Nephritis; Mice; Mice, Inbred NZB; Mycophenolic Acid; Proteinuria